Overview of signal transduction pathways

In biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another. Foundations of modern biology There are five unifying principles The cell is the structural and functional unit of all known living Organisms It is the smallest unit of an organism that is classified as living and is often called See also Electrophysiology In Biology, a signal or biopotential is an Electric quantity (voltage or current or field strength caused Most processes of signal transduction involve ordered sequences of biochemical reactions inside the cell, which are carried out by enzymes, activated by second messengers, resulting in a signal transduction pathway. Biochemistry is the study of the chemical processes in living Organisms It deals with the Structure and function of cellular components such as A chemical reaction is a process that always results in the interconversion of Chemical substances The substance or substances initially involved in a chemical reaction are called Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins In Cell physiology, a secondary messenger system (also known as a second messenger system) is a method of cellular signaling whereby a diffusable signaling molecule Such processes are usually rapid, lasting on the order of milliseconds in the case of ion flux, or minutes for the activation of protein- and lipid-mediated kinase cascades, but some can take hours, and even days (as is the case with gene expression), to complete. The number of proteins and other molecules participating in the events involving signal transduction increases as the process emanates from the initial stimulus, resulting in a "signal cascade," beginning with a relatively small stimulus that elicits a large response. A biochemical cascade is a series of Chemical reactions in which the products of one reaction are consumed in the next reaction This is referred to as amplification of the signal.

History

Occurrence of the term “signal transduction” The total number of papers published in each year since 1977 containing the specific phrase “signal transduction” in either their title or abstract section are plotted. These figures were extracted through an analysis of the papers contained within the MEDLINE database. MEDLINE ( Medical Literature Analysis and Retrieval System Online is a literature database of life sciences and biomedical information

The earliest published scientific paper recorded in the MEDLINE database as containing the specific term "signal transduction" within its text was published in 1972. Academic publishing describes the subfield of Publishing which distributes academic Research and Scholarship. MEDLINE ( Medical Literature Analysis and Retrieval System Online is a literature database of life sciences and biomedical information ^[1] Prior to 1977 articles can be found that use the term "signal transmission" or "sensory transduction" within their title or abstract. ^[2][3] However, it is not until 1977 that papers start to appear with the specific term "signal transduction" within their abstract, and 1979 before this specific term appears within a paper title. An abstract is a brief summary of a research article Thesis, review conference proceeding or any in-depth analysis of a particular subject or discipline ^[4][5] One source attributes the widespread use of the term signal transduction to a 1980 review article by Rodbell. ^[6][7]

As can be seen from the graph to the right, it is not until the late 1980s/early 1990s that research papers directly addressing signal transduction processes began to appear in large numbers in the scientific literature. Scientific literature comprises scientific Publications that report original empirical and theoretical work in the natural and Social sciences The occurrence of a specific term within the title or abstract of a scientific paper is usually a good indicator that the paper addresses a specifically related area of research. Scientific method refers to bodies of Techniques for investigating phenomena While there may be considered to be a number of landmark or important discoveries in the field of signal transduction, such as the link made by Rodbell between metabolic regulation and the activity of GTP and GTP-binding proteins,^[7] much of our current understanding of signal transduction processes is as a result of numerous contributions made to the field over many years by different research groups all over the world. Guanosine-5'-triphosphate ( GTP) is a Purine Nucleotide. One role is as substrate for the synthesis of RNA during transcription. Guanosine-5'-triphosphate ( GTP) is a Purine Nucleotide. One role is as substrate for the synthesis of RNA during transcription.

The total number of scientific papers related to signal transduction published since 1st Jan 1977 up to the 31st December 2007 was 48,377 of which only 11,211 were reviews of other papers

Signaling Molecules

Most signal transduction involves the binding of extracellular signaling molecules (or ligands) to cell-surface receptors that face outward from the plasma membrane and trigger events inside the cell. A review journal in Academic publishing is a periodical or series that is devoted to the publication of review articles that summarize the progress in some particular area or In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Also, intracellular signaling cascades can be triggered through cell-substratum interactions, as in the case of integrins, which bind ligands found within the extracellular matrix. Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells Steroids represent another example of extracellular signaling molecules that may cross the plasma membrane due to their lipophilic or hydrophobic nature. A steroid is a Terpenoid Lipid characterized by a Carbon skeleton with four fused rings generally arranged in a 6-6-6-5 fashion The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Lipophilicity, fat-liking, refers to the ability of a Chemical compound to dissolve in fats oils lipids and non-polar solvents such as Hexane or In Chemistry, hydrophobicity (from the combining form of water in Attic Greek hydro- and for fear phobos) refers to the physical property of ^[8] Many, but not all, steroids have receptors within the cytoplasm, and usually act by stimulating the binding of their receptors to the promoter region of steroid-responsive genes. The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. In Biology, a promoter is a region of DNA that facilitates the transcription of a particular Gene. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance ^[9] Within multicellular organisms, there is a diverse number of small molecules and polypeptides that serve to coordinate a cell's individual biological activity within the context of the organism as a whole. These molecules have been functionally classified as:

• hormones (e. Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body g. , melatonin),^[10]
• growth factors (e. Melatonin is a naturally occurring Hormone found in most animals including humans and some other living organisms including Algae. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. g. epidermal growth factor),^[11]
• extra-cellular matrix components (e. Epidermal growth factor or EGF is a Growth factor that plays an important role in the regulation of Cell growth, Proliferation, and In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells g. , fibronectin),^[12]
• cytokines (e. Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular g. , interferon-gamma),^[13]
• chemokines (e. Interferon-gamma ( IFN-γ) is a Dimerized soluble Cytokine that is the only member of the type II class of Interferons This interferon was originally Chemokines are a family of small Cytokines, or Proteins secreted by cells Proteins are classified as chemokines according to shared structural characteristics g. , RANTES),^[14]
• neurotransmitters (e. CCL5 (earlier called RANTES) is an 8kDa Protein classified as a chemotactic Cytokine or Chemokine. See Chemical synapse for an introduction to concepts and terminology used in this article g. , acetylcholine),^[15] and
• neurotrophins (e. The Chemical compound acetylcholine (often abbreviated ACh) is a Neurotransmitter in both the Peripheral nervous system (PNS and Central Neurotrophins are a family of proteins that induce the survival development and function of Neurons. g. , nerve growth factor). Nerve growth factor ( NGF) is a small secreted Protein which induces the differentiation and survival of particular target Neurons (nerve ^[16]

It is important to note that most of these classifications do not take into account the molecular nature of each class member. For example, as a class, neurotransmitters consist of neuropeptides such as endorphins^[17] and small molecules such as serotonin^[18] and dopamine. A neuropeptide is any of the variety of Peptides found in Neural tissue; e Endorphins are Endogenous Opioid Polypeptide compounds They are produced by the Pituitary gland and the Hypothalamus in Vertebrates Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates ^[19] Hormones are also a generic class of molecule able to initiate signal transduction, these include insulin (a polypeptide),^[20] testosterone (a steroid),^[21] and epinephrine (an amino acid derivative, in essence a small organic molecule). Insulin is a Hormone with intensive effects on both metabolism and several other body systems (eg vascular compliance Testosterone is a Steroid hormone from the Androgen group In mammals testosterone is primarily secreted in the testes of males and the Ovaries A steroid is a Terpenoid Lipid characterized by a Carbon skeleton with four fused rings generally arranged in a 6-6-6-5 fashion In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Organic chemistry is a discipline within Chemistry which involves the scientific study of the structure properties composition reactions, and preparation ^[22]

The classification of one molecule into one class of another is not exact. For example, epinephrine and norepinephrine secreted by the central nervous system act as neurotransmitters. Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. However, epinephrine when secreted by the adrenal medulla acts as a hormone. The adrenal medulla is part of the Adrenal gland. It is located at the center of the gland being surrounded by the Adrenal cortex. Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body

Environmental stimuli

In bacteria and other single-cell organisms, the variety of a signal transduction processes of which the cell is capable influences how many ways it can react and respond to its environment. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have In multicellular organisms, a multitude of different signal transduction processes are required for coordinating the behavior of individual cells to support the function of the organism as a whole. Multicellular organisms are Organisms consisting of more than one cell, and having Differentiated cells that perform specialized functions As may be expected, the more complex the organism, the more complex the repertoire of signal transduction processes the organism must possess. Thus, sensing of both the external and internal environments at the cellular level relies on signal transduction. Senses are the physiological methods of Perception. The senses and their operation classification and theory are overlapping topics studied by a variety of fields Many disease processes such as diabetes, heart disease, autoimmunity, and cancer arise from defects in signal transduction pathways, further highlighting the critical importance of signal transduction to biology, as well as medicine. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc Atherosclerosis is a Disease affecting arterial Blood vessels It is a chronic inflammatory response in the walls of arteries in large part due to the accumulation Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled

In addition to many of the regular signal transduction stimuli listed above, in complex organisms, there are also examples of additional environmental stimuli that initiate signal transduction processes. Environmental stimuli may also be molecular in nature (as above) or more physical, such as light striking cells in the retina of the eye,^[23] odorants binding to odorant receptors in the nasal epithelium,^[24] and bitter and sweet tastes stimulating taste receptors in the taste buds. The vertebrate retina is a light sensitive part inside the inner layer of the Eye. An olfactory receptor neuron also called an olfactory sensory neuron is the primary transduction cell in the Olfactory system. The olfactory epithelium is a specialized epithelial tissue inside the Nasal cavity that is involved in smell. G protein-coupled receptors ( GPCRs) also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and Taste buds are small structures on the upper surface of the Tongue, Soft palate, upper Esophagus and Epiglottis that provide information about ^[25] Certain microbial molecules, e. g. , viral nucleotides, bacterial lipopolysaccharides, and protein antigens, are able to elicit an immune system response against invading pathogens, mediated via signal transduction processes. Nucleotides are Organic compounds that consist of three joined structures a nitrogenous base a Sugar, and a Phosphate group Lipopolysaccharides ( LPS) are large Molecules consisting of a Lipid and a Polysaccharide joined by a Covalent bond; they are found An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor A pathogen (from Greek πάθος pathos "suffering passion" and γἰγνομαι (γεν- gignomai (gen- "I give birth to" infectious An immune response may occur independent of signal transduction stimulation by other molecules, as is the case for signal transduction via the Toll-like receptor or with help from stimulatory molecules located at the cell surface of other cells, as is the case for T-cell receptor signaling. Toll-like receptors ( TLRs) are a class of single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from Microbes The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells that is in general responsible for recognizing Antigens bound

Unicellular organisms may also respond to environmental stimuli via the activation of signal transduction pathways. For example, slime molds secrete cyclic-AMP upon starvation, which stimulates individual cells in the immediate environment to aggregate. The dictyostelids are a group of cellular Slime molds or social Amoebae When food (normally bacteria is readily available they take the form of individual amoebae Cyclic adenosine monophosphate ( cAMP, cyclic AMP or 3'-5'-cyclic Adenosine monophosphate) is a Second messenger that is important in many biological ^[26] Yeast also use mating factors to determine the mating types of other yeast and participate in sexual reproduction. Yeasts are a growth form of eukaryotic Microorganisms classified in the kingdom Fungi, with about 1500 Species currently described The yeast Saccharomyces cerevisiae is a simple single celled Eukaryote with both a Diploid and Haploid mode of existence ^[27]

Cellular responses

Activation of genes,^[28] alterations in metabolism,^[29] the continued proliferation and death of the cell,^[30] and the stimulation or suppression of locomotion,^[31] are some of the cellular responses to extracellular stimulation that require signal transduction. Transcription is the synthesis of RNA under the direction of DNA History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. Cell division is a process by which a cell, called the parent cell divides into two or more cells called daughter cells. Chemotaxis, a kind of Taxis, is the phenomenon in which bodily cells bacteria, and other single-cell or Multicellular organisms direct their movements Gene activation leads to further cellular effects, since the protein products of many of the responding genes include enzymes and transcription factors themselves. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins In the field of Molecular biology, a transcription factor (sometimes called a sequence-specific DNA binding factor is a Protein that binds to specific sequences Transcription factors produced as a result of a signal transduction cascade can, in turn, activate yet more genes. Therefore an initial stimulus can trigger the expression of an entire cohort of genes, and this, in turn, can lead to the activation of any number of complex physiological events. These events include the increased uptake of glucose from the blood stream stimulated by insulin^[29] and the migration of neutrophils to sites of infection stimulated by bacterial products. Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. Insulin is a Hormone with intensive effects on both metabolism and several other body systems (eg vascular compliance Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of White blood cells in humans and form an essential part of the The set of genes and the order in which they are activated in response to stimuli are often referred to as a genetic program. In Biology, a genetic program of a cell is a physiological change brought about by a temporal pattern of activation of a particular subset of Genes ^[32]

Neurotransmitters are ligands that are capable of binding to ion channel proteins, resulting in their opening to allow the rapid flow of a particular ion across the plasma membrane. See Chemical synapse for an introduction to concepts and terminology used in this article Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living ^[15] This results in an altering of the cell's membrane potential and is important for processes such as the neural conduction of electrochemical impulses. Membrane potential (or transmembrane potential) is the Voltage difference (or Electrical potential difference between the interior and exterior of a Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information Ligands can be freely soluble,^[11] or can be found on the surface of other cells or within the extracellular matrix. Epidermal growth factor or EGF is a Growth factor that plays an important role in the regulation of Cell growth, Proliferation, and In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells ^[12] Such cell surface or extracellular matrix ligands signal between cells when they come in contact with each other, such as when a phagocytic cell presents antigens to lymphocytes, or upon adhesion to the extracellular matrix, as when integrins at the cell surface of fibroblasts engage fibronectin. Dendritic cells (DCs are Immune cells and form part of the Mammalian Immune system. An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells that is in general responsible for recognizing Antigens bound Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. A fibroblast is a type of cell that synthesizes and maintains the Extracellular matrix of many Animal tissues Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins ^[33]

Most mammalian cells require stimulation to control not only cell division but also survival. In the absence of growth factor stimulation, programmed cell death ensues in most cells. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. Such requirements for extra-cellular stimulation are necessary for controlling cell behavior in the context of both unicellular and multi-cellular organisms. Signal transduction pathways are perceived to be so central to biological processes that it is not surprising that a large number of diseases have been attributed to their dysregulation.

Discussed below are how signal transduction via various classes of receptor may lead to the above cellular responses.

Types of receptor

Receptors can be roughly divided into two major classes:

1. Intracellular receptors and
2. Cell-surface receptors. Not to be confused with Intercellular, meaning "between cells" The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer

Ligand-gated ion channel receptors are a class of receptor that may occur both at the cell-surface or intracellularly. The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are Not to be confused with Intercellular, meaning "between cells"

Receptors that are solely intracellular include those for steroid hormones, thyroid hormone, retinoic acid, and derivatives of vitamin D₃. Not to be confused with Intercellular, meaning "between cells" Steroid hormones are Steroids which act as Hormones Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind The thyroid hormones, Thyroxine ( T4) and Triiodothyronine ( T3) are Tyrosine -based Hormones produced Vitamin D is a group of fat-soluble Prohormones, the two major forms of which are vitamin D2 (or Ergocalciferol) and vitamin D3 (or In contrast to ligands that bind to cell surface receptors, in order to initiate signal transduction these ligands must cross the cell membrane. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer See the intracellular receptors section below for more details. In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another

Cell-surface receptors

Cell-surface receptors are integral transmembrane proteins and recognize the vast majority of extracellular signaling molecules. A transmembrane protein is a Protein that spans the entire Biological membrane. Transmembrane receptors span the plasma membrane of the cell, with one part of the receptor on the outside of the cell (the extracellular domain), and the other on the inside of the cell (the intracellular domain). Transmembrane receptors are Integral membrane proteins which reside and operate typically within a cell's Plasma membrane, but also in the membranes of The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Signal transduction occurs as a result of stimulatory molecule or the binding of a ligand to its extracellular domain; the ligand itself does not pass through the plasma membrane prior to receptor-binding. In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule

Binding of a ligand to a cell-surface receptor stimulates a series of events inside the cell, with different types of receptor stimulation of different intracellular responses. Receptors typically respond to only the binding of a specific ligand. In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule Upon binding, the ligand initiates the transmission of a signal across the plasma membrane by inducing a change in the shape or conformation of the intracellular part of the receptor (see this link [2]for a molecular model for receptor activation). In Chemistry, conformational isomerism is a form of Stereoisomerism in which Molecules with the same Structural formula (same connectivity Often, such changes in conformation either result in the activation of an enzymatic activity contained within the receptor or expose a binding site for other signaling proteins within the cell. Once these proteins bind to the receptor, they themselves may become active and propagate the signal into the cytoplasm.

In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity. Animals Plants fungi, and Protists are eukaryotes (juːˈkærɪɒt or -oʊt Organisms whose cells are organized into complex These enzymes include tyrosine kinase, heterotrimeric G proteins, small GTPases, various serine/threoine protein kinases, phosphatases, lipid kinases, and hydrolases. A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. GTP chemical structurepng|thumb|180px| Guanosine triphosphate]] G proteins short for guanine nucleotide-binding proteins, are a family of Proteins involved In Biology, small GTPases are small (20-25 kDa Proteins that bind to guanosine triphosphate ( GTP) A protein kinase is a Kinase Enzyme that modifies other Proteins by chemically adding Phosphate groups to them ( Phosphorylation) A phosphatase is an Enzyme that removes a Phosphate group from its Substrate by hydrolysing Phosphoric acid mono Esters into Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks are a family of related enzymes that are capable of phosphorylating the 3 position Hydroxyl group of the Inositol Phospholipase C is a class of Enzymes that cleave Phospholipids just before the Phosphate group (see Figure Some receptor-stimulated enzymes create specific second messengers including cyclic nucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), Phosphatidylinositol derivatives, such as Phosphatidylinositol-triphosphate (PIP₃), Diacylglycerol (DAG) and Inositol-triphosphate (IP₃), IP₃, controlling the release of intracellular calcium stores into the cytoplasm (see second messengers section later in this article). In Cell physiology, a secondary messenger system (also known as a second messenger system) is a method of cellular signaling whereby a diffusable signaling molecule A cyclic nucleotide is any Nucleotide in which the Phosphate group is bonded to two of the Sugar 's hydroxyl groups forming a cyclical or ring structure Cyclic adenosine monophosphate ( cAMP, cyclic AMP or 3'-5'-cyclic Adenosine monophosphate) is a Second messenger that is important in many biological Cyclic guanosine monophosphate ( cGMP) is a Cyclic nucleotide derived from Guanosine triphosphate (GTP Phosphatidylinositol (abbreviated PtdIns or PI is a minor Phospholipid component in the cytosolic side of eukaryotic Cell membranes. Phosphatidylinositol (345-trisphosphate (PtdIns(345 P 3 commonly abbreviated to PIP3 is the product of the class I Phosphoinositide A diglyceride, or a diacylglycerol (DAG is a Glyceride consisting of two Fatty acid chains covalently bonded to a Glycerol In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another Other activated proteins interact with adapter proteins. An adaptor protein is a Protein which is accessory to main proteins in a Signal transduction pathway Adapter proteins facilitate interactions between other signaling proteins, and coordinate the formation of signaling complexes necessary to produce an appropriate cellular response to a particular stimulus. Enzymes and adapter proteins are both responsive to various second messenger molecules.

Many of the enzymes activated as part of the signal transduction mechanism and also many adapter proteins have been found to possess specialized protein domains that bind to specific secondary messenger molecules. A protein domain is a part of protein sequence and structure that can evolve, function and exist independently of the rest of the protein chain For example, calcium ions bind specifically to the EF hand domains of calmodulin, allowing this molecule to bind and activate Calmodulin-dependent kinase. The EF hand is a Helix-turn-helix Structural domain found in a large family of calcium-binding Proteins It consists of two alpha helices Calmodulin ( CaM) (an abbreviation for CAL cium MODUL ated prote' IN') is a calcium-binding protein expressed in all Eukaryotic cells PIP₃, PIP₂ and other phosphoinositides may bind to the Pleckstrin homology domains of proteins such as the kinase protein AKT again with activation activity. Pleckstrin homology domain (PH domain is a Protein domain of approximately 120 Amino acids that occurs in a wide range of proteins involved in intracellular signaling Akt1, also known as "Akt" or Protein kinase B (PKB is an important molecule in mammalian cellular signaling

There are many different classes of transmembrane receptor that recognize different extracellular signaling molecules. Specific example receptors discussed in this article are:

1. G-protein coupled receptors, e. G protein-coupled receptors ( GPCRs) also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and g. , Chemokine receptors
2. Receptor tyrosine kinases, e. Chemokines are a family of small Cytokines, or Proteins secreted by cells Proteins are classified as chemokines according to shared structural characteristics Receptor tyrosine kinases (RTKs are the high affinity Cell surface receptors for many polypeptide Growth factors Cytokines and Hormones g. , Growth factor receptors,
3. Integrins
4. Toll-like receptors

Further examples are given in the transmembrane receptor article. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. Toll-like receptors ( TLRs) are a class of single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from Microbes Transmembrane receptors are Integral membrane proteins which reside and operate typically within a cell's Plasma membrane, but also in the membranes of

G-protein-coupled receptors

For more details on this topic, see G-protein-coupled receptor. G protein-coupled receptors ( GPCRs) also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and

Signal transduction from a G-protein-linked receptor following interaction with its hormone ligand

G-protein-coupled receptors (GPCRs) are a family of integral membrane proteins that possess seven membrane-spanning domains, and are linked to a guanine nucleotide-binding protein (or heterotrimeric G protein). An Integral Membrane Protein ( IMP) is a Protein Molecule (or assembly of proteins that is permanently attached to the Biological membrane. GTP chemical structurepng|thumb|180px| Guanosine triphosphate]] G proteins short for guanine nucleotide-binding proteins, are a family of Proteins involved Many receptors make up this family, including adrenergic receptors, neurotransmitter receptors, olfactory receptors, opioid receptors, chemokine receptors, and rhodopsin. The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the Catecholamines Adrenergic receptors Olfactory receptors expressed in the Cell membranes of Olfactory receptor neurons are responsible for the detection of Odor molecules Opioid receptors are a group of G-protein coupled receptors with Opioids as Ligands The Endogenous Opioids are Dynorphins Chemokine receptors are Cytokine receptors found on the surface of certain cells which interact with a type of Cytokine called a Chemokine. Rhodopsin, also known as visual purple, is a Pigment of the Retina that is responsible for both the formation of the Photoreceptor cells and the

Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor. An inactive G protein exists as a heterotrimer, a molecule composed of three different protein subunits: Gα, Gβ, and Gγ. Once the GPCR recognizes a ligand, the shape (conformation) of the receptor changes to mechanically activate the G protein, and causes one subunit (Gα) to bind a molecule of GTP (causing activation) and dissociate from the other two G-protein subunits (Gβ and Gγ); the dissociation exposes sites on the G-protein subunits that interact with other molecules. ^[34] The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins, including phosphodiesterases and adenylyl cyclases, phospholipases, and ion channels that permit the release of second messenger molecules such as cyclic-AMP (cAMP), cyclic-GMP (cGMP), inositol triphosphate (IP3), diacylglycerol (DAG), and calcium (Ca²⁺) ions. A phosphodiesterase is any Enzyme that breaks a Phosphodiester bond. Adenylate cyclase ( also known as adenylyl cyclase or AC) is a Lyase Enzyme. A phospholipase is an enzyme that converts Phospholipids into Fatty acids and other Lipophilic substances Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living Cyclic adenosine monophosphate ( cAMP, cyclic AMP or 3'-5'-cyclic Adenosine monophosphate) is a Second messenger that is important in many biological Cyclic guanosine monophosphate ( cGMP) is a Cyclic nucleotide derived from Guanosine triphosphate (GTP Inositol trisphosphate or inositol 145-trisphosphate (also commonly known as triphosphoinositol; abbreviated InsP3 or IP3 Calcium (Ca2+ plays a vital role in the Anatomy, Physiology and Biochemistry of Organisms and of the cell, particularly ^[35] For example, a rhodopsin molecule in the plasma membrane of a retina cell in the eye that was activated by a photon can activate up to 2000 effector molecules (in this case, transducin) per second. Rhodopsin, also known as visual purple, is a Pigment of the Retina that is responsible for both the formation of the Photoreceptor cells and the The vertebrate retina is a light sensitive part inside the inner layer of the Eye. Eyes are organs that detect Light, and send signals along the Optic nerve to the visual areas of the brain In Physics, the photon is the Elementary particle responsible for electromagnetic phenomena Transducin (also called Gt is a heterotrimeric G protein that is naturally expressed in Vertebrate Retina rods and cones (a different

The total strength of signal amplification by a GPCR is determined by:

• The lifetime of the ligand-receptor-complex. If the ligand-receptor-complex is stable, it takes longer for the ligand to dissociate from its receptor, thus the receptor will remain active for longer and will activate more effector proteins.
• The amount and lifetime of the receptor-effector protein-complex. The more effector protein is available to be activated by the receptor, and the faster the activated effector protein can dissociate from the receptor, the more effector protein will be activated in the same amount of time.
• Deactivation of the activated receptor. A receptor that is engaged in a hormone-receptor-complex can be deactivated, either by covalent modification (for example, phosphorylation) or by internalization (see ubiquitin). Ubiquitin is a highly-conserved regulatory Protein that is ''ubiquitously'' expressed in Eukaryotes.
• Deactivation of effectors through intrinsic enzymatic activity. Either small or large G-proteins possess intrinsic GTPase activity, which controls the duration of the triggered signal. This activity may be increased through the action of other proteins such as GTPase-activating proteins (GAPS). GTPase Activating Protein s or GAPs, or GTPase Accelerating Protein s is a family of regulatory proteins whose members can bind to activated G proteins and

The idea that G-protein-coupled receptors, to be specific, chemokine receptors, participate in cancer development is suggested by a study wherein a point mutation was inserted into the gene encoding the chemokine receptor CXCR2. A point mutation, or single base substitution, is a type of Mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Chemokines are a family of small Cytokines, or Proteins secreted by cells Proteins are classified as chemokines according to shared structural characteristics Cells transfected with the CXCR2 mutant underwent a malignant transformation. Transfection is the process of introducing nucleic acids into cells by non-viral methods. A mutant is an individual organism or new genetic character arising or resulting from an instance of Mutation, which is a base-pair sequence change within the DNA Malignant transformation is the process by which cells acquire the properties of Cancer. ^[36] The result of the point mutation was the expression of CXCR2 in an active conformation, despite the absence of chemokine-binding (the CXCR2 mutant is said to be "constitutively active"). A point mutation, or single base substitution, is a type of Mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic Gene expression is the process by which inheritable information from a Gene, such as the DNA sequence, is made into a functional Gene product, such

Receptor Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligand. Receptor tyrosine kinases (RTKs are the high affinity Cell surface receptors for many polypeptide Growth factors Cytokines and Hormones In Chemistry and Biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of Enzyme that transfers Phosphate In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally There are many RTK proteins that are classified into subfamilies depending on their structural properties and ligand specificity. These include many growth factor receptors such as insulin receptor and the insulin-like growth factor receptors, and many others receptors. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. Insulin is a Hormone with intensive effects on both metabolism and several other body systems (eg vascular compliance ^[37] To conduct their biochemical signals, RTKs need to form dimers in the plasma membrane^[38]. A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer The dimer is stabilized by ligand binding by the receptor. Interaction between the two cytoplasmic domains of the dimer is thought to stimulate autophosphorylation of tyrosines within the cytoplasmic tyrosine kinase domains of the RTKs causing their conformational changes. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize The kinase domain of the receptors is subsequently activated, initiating signaling cascades of phosphorylation of downstream cytoplasmic molecules. Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule These signals are essential to various cellular processes, such as control of cell growth, differentiation, metabolism, and migration. In Developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized Cell type. Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. Cell migration is a central process in the development and maintenance of Multicellular organisms Tissue formation during embryonic development, Wound healing ^[37]

As is the case with G-Protein-coupled receptors, proteins that bind GTP play a major role in transmission of signal from the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Ral families, referred to collectively as small G proteins. In Biology, small GTPases are small (20-25 kDa Proteins that bind to guanosine triphosphate ( GTP) These proteins act as molecular switches that are usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Thus, upon activation, they are responsible for the recruitment of proteins to specific membrane subdomains where they participate in signaling. Activated RTKs, in turn, activate small G proteins, which in turn activate Guanine Nucleotide Exchange Factors, such as SOS1. Guanine nucleotide exchange factors (GEFs are components of Intracellular signalling networks. Son of sevenless homolog 1 (Drosophila, also known as SOS1, is a human Gene. Once activated, these exchange factors can activate many more small G-proteins, thus amplifying the receptors initial signal.

As with the mutation of G-protein coupled receptors, the mutation of certain RTK genes can result in the expression of receptors that exist in a constitutively-activate state. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Gene expression is the process by which inheritable information from a Gene, such as the DNA sequence, is made into a functional Gene product, such Such mutated RTK genes may act as oncogenes, genes that contribute to the initiation or progression of cancer. An oncogene is a protein encoding Gene, which — when deregulated — participates in the onset and development of Cancer. Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled ^[39]

Integrins

For more details on this topic, see Integrin. Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals.

An overview of integrin-mediated signal transduction, adapted from Hehlgens et al (2007). ^[40]

Integrins are produced by a wide variety of cell types, and play a role in the attachment of a cell to the extracellular matrix (ECM) and to other cells, and in the signal transduction of signals received from extracellular matrix components such as fibronectin, collagen, and laminin. A cell type is a distinct morphological or functional form of cell. In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein Laminin is the major non-collagenous component of the Basal lamina, such as those on which cells of an Epithelium sit Ligand-binding to the extracellular domain of integrins induces a conformational change within the protein and a clustering of the protein at the cell surface, in order to initiate signal transduction. Integrins lack kinase activity, and integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules such as integrin-linked kinase (ILK), focal-adhesion kinase (FAK), talin, paxillin, parvins, p130Cas, Src-family kinases, and GTPases of the Rho family, the main protein coordinating signal transduction being ILK. Integrin-linked kinase (ILK is a 59kDa protein originally identified while conducting a yeast-two hybrid screen with integrin β1 as the bait protein (Hannigan et al Talin ( Armenian: Թալին is a city in the Aragatsotn province of Armenia. Paxillin is a Signal transduction Adaptor protein and should be not be confused with the Neurotoxin Paxilline. Src is a family of proto-oncogenic Tyrosine kinases originally discovered by J GTPases (singular GTPase are a large family of Hydrolase Enzymes that can bind and hydrolyze guanosine triphosphate (GTP. Integrin-linked kinase (ILK is a 59kDa protein originally identified while conducting a yeast-two hybrid screen with integrin β1 as the bait protein (Hannigan et al ^[40] As shown in the overview to the right, cooperative integrin and receptor tyrosine kinase signaling determine cellular survival, apoptosis, proliferation, and differentiation.

Important differences exist between integrin-signaling in circulating blood cells and that in non-circulating blood cells such as epithelial cells. In biology and medicine epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout the body Integrins at the cell-surface of circulating cells are inactive under normal physiological conditions. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Physiology (from Greek grc φύσις physis, "nature origin" and grc -λογία -logia) is the study of the mechanical physical For example, cell-surface integrins on circulating leukocytes are maintained in an inactive state in order to avoid epithelial cell attachment. Only in response to appropriate stimuli are leukocyte integrins converted into an active form, such as those received at the site of an inflamatory response. Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens In a similar manner, it is important that integrins at the cell surface of circulating platelets are kept in an inactive state under normal conditions, in order to avoid thrombosis. Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved Thrombosis is the formation of a blood Clot ( Thrombus) inside a Blood vessel, obstructing the flow of Blood through the Circulatory Epithelial cells, in contrast, have active integrins at their cell surface under normal conditions, which help to maintain their stable adhesion to underlying stromal cells, which provide appropriate signals in order to maintain their survival and differentiation. ^[41]

Toll-Like Receptors

For more details on this topic, see toll-like receptor. Toll-like receptors ( TLRs) are a class of single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from Microbes

When activated, Toll-like receptors (TLRs) recruit adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram. Myeloid differentiation primary response gene (88 (MYD88 is a universal Adapter protein as it is used by all TLRs (except TLR 3) to activate Transcription Tirap can refer to Tirap district, a district in Arunachal Pradesh bordering Myanmar, Nagaland and Assam TIR-domain-containing adapter-inducing interferon-β ( TRIF) is is an adapter in responding to activation of Toll-like receptors (TLRs ^[42][43][44] The adapters activate other molecules within the cell, including certain protein kinases (IRAK1,IRAK4, TBK1, and IKKi) that amplify the signal, and ultimately lead to the induction or suppression of genes that orchestrate the inflammatory response. Interleukin-1 receptor-associated kinase 1, also known as IRAK1, is a human Gene. IRAK-4 (interleukin-1 receptor-associated kinase 4 in the IRAK family is a Protein kinase involved in signaling innate immune responses from Toll-like receptors TANK-binding kinase 1, also known as TBK1, is a human Gene. In all, thousands of genes are activated by TLR signaling, and, together, the TLRs constitute one of the most powerful and important gateways for gene modulation.

Ligand-gated ion channel receptors

For more details on this topic, see ligand gated ion channel. The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are

A ligand-activated ion channel will recognize its ligand, and then undergo a structural change that opens a gap (channel) in the plasma membrane through which ions can pass. These ions will then relay the signal. An example for this mechanism is found in the receiving cell, or post-synaptic cell of a neural synapse. Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands

By contrast, other ion channels open in response to a change in cell potential, that is, the difference of the electrical charge across the membrane. The Membrane potential, or better Membrane Voltage, is the difference of Electric potentials between two Aqueous solutions separated by a ( Electric charge is a fundamental conserved property of some Subatomic particles which determines their Electromagnetic interaction. In neurons, this mechanism underlies the action potentials that travel along nerves. Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal A nerve is an enclosed cable-like bundle of peripheral Axons (the long slender projections of Neurons. The influx of ions that occurs in response to ligand-gated ion channels often induce action potentials by depolarizing the membrane of the post-synaptic cells, which results in the wave-like opening of voltage-gated ion channels. In addition, calcium ions are also commonly allowed into the cell during ligand-induced ion channel opening. This calcium can act as a classical second messenger, setting in motion signal transduction cascades and altering the cellular physiology of the responding cell. This may result in strengthening of the synapse between the pre- and post-synaptic cells by remodeling the dendritic spines involved in the synapse. A dendritic spine (or spine is a small membranous protrusion from a neuron's Dendrite that typically receives input from a single Synapse

Intracellular receptors

Further information: Intracellular receptor

Intracellular receptors include nuclear receptors and cytoplasmic receptors, and are soluble proteins localized within the nucleoplasm or the cytoplasm, respectively. Intracellular receptors are receptors located inside the cell rather than on its Cell membrane. In the field of Molecular biology, nuclear receptors are a class of Proteins found within the interior of cells that are responsible for sensing the presence of Similar to the Cytoplasm of a cell, the nucleus contains nucleoplasm or nuclear sap. The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. The typical ligands for nuclear receptors are lipophilic hormones, with steroid hormones (for example, testosterone, progesterone, and cortisol) and derivatives of vitamin A and D among them. Lipophilicity, fat-liking, refers to the ability of a Chemical compound to dissolve in fats oils lipids and non-polar solvents such as Hexane or A steroid is a Terpenoid Lipid characterized by a Carbon skeleton with four fused rings generally arranged in a 6-6-6-5 fashion Testosterone is a Steroid hormone from the Androgen group In mammals testosterone is primarily secreted in the testes of males and the Ovaries Progesterone is a C-21 Steroid Hormone involved in the Female Menstrual cycle, Pregnancy (supports Gestation Cortisol is a Corticosteroid Hormone produced by the Adrenal gland (in the Zona fasciculata of the Adrenal cortex) A vitamin is an Organic compound required as a Nutrient in tiny amounts by an Organism. In order to reach its receptor and initiate signal transduction, the hormone must pass through the plasma membrane, usually by passive diffusion. The nuclear receptors are ligand-activated transcription activators; on binding with the ligand (the hormone), the ligands will pass through the nuclear membrane into the nucleus and enable the transcription of a certain gene and, thus, the production of a protein. In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally Transcription is the synthesis of RNA under the direction of DNA The nuclear envelope (NE(also known as the perinuclear envelope, nuclear membrane, nucleolemma or karyotheca) is a double lipid bilayer that In Cell biology, the nucleus (pl nuclei; from Latin la ''nucleus'' or la ''nuculeus'' "little nut" or kernel is a membrane-enclosed History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance

The nuclear receptors that were activated by the hormones attach at the DNA at receptor-specific Hormone-Responsive Elements (HREs), DNA sequences that are located in the promoter region of the genes that are activated by the hormone-receptor complex. In Biology, a promoter is a region of DNA that facilitates the transcription of a particular Gene. As this enables the transcription of the according gene, these hormones are also called inductors of gene expression. Gene expression is the process by which inheritable information from a Gene, such as the DNA sequence, is made into a functional Gene product, such The activation of gene transcription is much slower than signals that directly affect existing proteins. As a consequence, the effects of hormones that use nucleic receptors are usually long-term. Although the signal transduction via these soluble receptors involves only a few proteins, the details of gene regulation are yet not well understood. The nucleic receptors all have a similar, modular structure:

N-AAAABBBBCCCCDDDDEEEEFFFF-C

where CCCC is the DNA-binding domain that contains zinc fingers, and EEEE the ligand-binding domain. A zinc finger is a large superfamily of Protein domains that can bind to DNA. The latter is also responsible for dimerization of most nuclearic receptors prior to DNA binding. A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces As a third function, it contains structural elements that are responsible for transactivation, used for communication with the translational apparatus. Transactivation is an increased rate of gene expression triggered either by endogenous cellular or viral proteins - transactivators. The zinc fingers in the DNA-binding domain stabilize DNA binding by holding contact to the phosphate backbone of the DNA. The DNA sequences that match the receptor are usually hexameric repeats, either normal, inverted, or everted. The sequences are quite similar, but their orientation and distance are the parameters by which the DNA-binding domains of the receptors can tell them apart.

Steroid receptors are a subclass of nuclear receptors, located primarily within the cytosol. Steroid hormone receptors are Intracellular receptors (typically Cytoplasmic that perform Signal transduction for Steroid hormones Steroid In the absence of steroid hormone, the receptors cling together in a complex called an aporeceptor complex, which also contains chaperone proteins (also known as heatshock proteins or Hsps). This article is about the protein For other uses see Chaperone, a disambiguation page Heat shock proteins ( HSP) are a group of Proteins whose expression is increased when the cells are exposed to elevated temperatures or other stress The Hsps are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence that enables its passage into the nucleus is accessible. Protein folding is the physical process by which a Polypeptide folds into its characteristic and functional three-dimensional structure.
Steroid receptors can also have a repressive effect on gene expression, when their transactivation domain is hidden so it cannot activate transcription. Furthermore, steroid receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal end, as a result of another signal transduction pathway, for example, a by a growth factor. Serine (abbreviated as Ser or S) is an Organic compound with the formula H[[oxygen O]]2 CCH NH sub>2CH2OH The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. This behaviour is called crosstalk. In Biology, the term crosstalk refers to the phenomenon that signal components in Signal transduction can be shared between different signal pathways and responses

RXR- and orphan-receptors These nuclear receptors can be activated by

• a classic endocrine-synthesized hormone that entered the cell by diffusion
• a hormone that was built within the cell (for example, retinol) from a precursor or prohormone, which can be brought to the cell through the bloodstream
• a hormone that was completely synthesized within the cell, for example, prostaglandin. The retinoic acid receptor (RAR is a type of Nuclear receptor which is activated by both All-trans retinoic acid and 9-cis retinoic acid. Retinol (Afaxin, the animal form of Vitamin A, is a fat-soluble vitamin important in vision and Bone growth A protein precursor, also called a pro-protein or pro-peptide, is an inactive Protein (or Peptide) that can be turned into an active form by A prohormone is a substance that is a precursor to a Hormone, usually having minimal hormonal effect by itself A prostaglandin is any member of a group of Lipid compounds that are derived enzymatically from Fatty acids and have important functions in the Animal body

These receptors are located in the nucleus and are not accompanied by chaperone proteins. In the absence of hormone, they bind to their specific DNA sequence, repressing the gene. Upon activation by the hormone, they activate the transcription of the gene that they were repressing.

Certain intracellular receptors of the immune system are examples of cytoplasmic receptors. An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor Recently-identified NOD like receptors (NLRs) reside in the cytoplasm of specific eukaryotic cells and interact with particular ligands, such as microbial molecules, using a leucine-rich repeat (LRR) motif that is similar to the ligand-binding motif of the extracellular receptors known as TLRs. Pattern recognition receptors, or PRR s are Proteins expressed by cells of the Immune system to identify molecules associated with microbial Pathogens Animals Plants fungi, and Protists are eukaryotes (juːˈkærɪɒt or -oʊt Organisms whose cells are organized into complex A leucine-rich repeat (LRR is a Protein Structural motif that forms an α/β horseshoe fold. Some of these molecules (e. g. , NOD1 and NOD2) interact with an enzyme called RICK kinase (or RIP2 kinase) that activates NF-κB signaling, whereas others (e. NF-κB ( nuclear factor-kappa B) is a protein complex that is a Transcription factor. g. , NALP3) interact with inflammatory caspases (e. Caspases, or c ysteine- asp artic acid prote ases, are a family of Cysteine proteases which play essential roles in Apoptosis (programmed g. , caspase 1) and initiate processing of particular cytokines (e. Caspase 1 is an Enzyme that proteolytically cleaves other proteins such as the precursor forms of the inflammatory Cytokines interleukin Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular g. , interleukin-1β). Interleukin-1 (IL-1 is one of the first Cytokines ever described ^[45] Similar receptors exist inside plant cells and are called Plant R Proteins. Another type of cytoplasmic receptor also has a role in immune surveillance. These receptors are known as RNA Helicases and include RIG-I, MDA5, and LGP2. ^[46]

Second Messengers

Intracellular signal transduction is largely carried out by second messenger molecules. In Cell physiology, a secondary messenger system (also known as a second messenger system) is a method of cellular signaling whereby a diffusable signaling molecule

Ca²⁺ concentration is usually maintained at a very low level in the cytosol by sequestration in the smooth endoplasmic reticulum and the mitochondria. Ca²⁺ release from the endoplasmic reticulum into the cytosol results in the binding of the released Ca²⁺ to signaling proteins that are then activated. The cytosol or intracellular fluid (or cytoplasmic matrix) is the liquid found inside cells. There are two combined receptor/ion channel proteins that perform the task of controlled transport of Ca²⁺:

• The InsP₃-receptor will transport Ca²⁺ upon interaction with inositol triphosphate (thus the name) on its cytosolic side. Inositol trisphosphate or inositol 145-trisphosphate (also commonly known as triphosphoinositol; abbreviated InsP3 or IP3 It consists of four identical subunits.
• The ryanodine receptor is named after the plant alkaloid ryanodine. Ryanodine receptors ( RyRs) form a class of intracellular Calcium channels in various forms of excitable animal tissue like Muscles and Neurons Plants are living Organisms belonging to the kingdom Plantae. This article is about the chemical compounds alkaloids For the Pharmaceutical company in the Republic of Macedonia see Alkaloid (company. Ryanodine is a poisonous Alkaloid found in the South American plant Ryania speciosa (Flacourtiaceae It is similar to the InsP₃ receptor and stimulated to transport Ca²⁺ into the cytosol by recognizing Ca²⁺ on its cytosolic side, thus establishing a feedback mechanism; a small amount of Ca²⁺ in the cytosol near the receptor will cause it to release even more Ca²⁺. Feedback is a circular causal Process whereby some proportion of a system's output is returned (fed back to the Input. It is especially important in neurons and muscle cells. Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information Skeletal muscle is a type of Striated muscle, which usually attaches to tendons In heart and pancreas cells, another second messenger (cyclic-ADP ribose) takes part in the receptor activation. The heart is a muscular organ in all Vertebrates responsible for pumping Blood through the Blood vessels by repeated rhythmic The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. The localized and time-limited activity of Ca²⁺ in the cytosol is also called a Ca²⁺ wave. Once released into the cytosol from intracellular stores or extracellular sources, Ca²⁺ acts as a signal molecule within the cell. This works by tightly limiting the time and space when Ca²⁺ is free (and thus active). Therefore, the concentration of free Ca²⁺ within the cell is usually very low; it is stored within organelles, usually the endoplasmic reticulum (sarcoplasmic reticulum in muscle cells), where it is bound to molecules like calreticulin. In Cell biology, an organelle (pronunciation /ɔː(rgəˡnɛl/ is a specialized subunit within a cell that has a specific function and is usually separately enclosed The endoplasmic reticulum (Greek endo = "within" (prefix plásma = "formed entity" Latin reticulum = "little net" or ER, is an Organelle The endoplasmic reticulum (Greek endo = "within" (prefix plásma = "formed entity" Latin reticulum = "little net" or ER, is an Organelle Calreticulin is a multifunctional Protein that binds Ca2+ Ions (a Second messenger Molecule in Signal transduction

Ca²⁺ is used in a multitude of processes, among them muscle contraction, release of neurotransmitter from nerve endings, vision in retina cells, proliferation, secretion, cytoskeleton management, cell migration, gene expression, and metabolism. Muscle (from Latin musculus, diminutive of mus "mouse" is contractile tissue of the body and is derived from the In Psychology, visual perception is the ability to interpret information from Visible light reaching the Eyes The resulting Perception is also The vertebrate retina is a light sensitive part inside the inner layer of the Eye. The term cell growth is used in two different ways in Biology. Secretion is the process of segregating elaborating and releasing chemicals from a cell, or a secreted Chemical substance or amount of substance cytoskeleton (also CSK is a cellular " Scaffolding " or " Skeleton " contained within the Cytoplasm. Cell migration is a central process in the development and maintenance of Multicellular organisms Tissue formation during embryonic development, Wound healing Gene expression is the process by which inheritable information from a Gene, such as the DNA sequence, is made into a functional Gene product, such Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. The three main pathways that lead to Ca²⁺ activation are :

1. G protein-regulated pathways
2. Pathways regulated by receptor-tyrosine kinases
3. Ligand- or current-regulated ion channels

There are two different ways by which Ca²⁺ can regulate proteins:

1. A direct recognition of Ca²⁺ by the protein
2. Binding of Ca²⁺ in the active site of an enzyme. GTP chemical structurepng|thumb|180px| Guanosine triphosphate]] G proteins short for guanine nucleotide-binding proteins, are a family of Proteins involved A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living The active site of an Enzyme contains the catalytic and Binding sites. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins

One of the best-studied interactions of Ca²⁺ with a protein is the regulation of calmodulin by Ca²⁺. Calmodulin ( CaM) (an abbreviation for CAL cium MODUL ated prote' IN') is a calcium-binding protein expressed in all Eukaryotic cells Calmodulin itself can regulate other proteins, or be part of a larger protein (for example, phosphorylase kinase). Phosphorylase kinase is a Serine/threonine-specific protein kinase which converts Glycogen phosphorylase b to glycogen phosphorylase a activating it to release The Ca²⁺/calmodulin complex plays an important role in proliferation, mitosis, and neural signal transduction. Mitosis is the process in which a Eukaryotic cell separates the Chromosomes in its Cell nucleus, into two identical sets in two daughter nuclei

Lipophilic second messenger molecules - These molecules are all derived from lipids that normally reside in cellular membranes. Enzymes stimulated by activated receptors modify these lipids, converting them into second messengers. One example of lipophilic second messenger molecule is diacylglycerol, required for the activation of protein kinase C. Lipophilicity, fat-liking, refers to the ability of a Chemical compound to dissolve in fats oils lipids and non-polar solvents such as Hexane or A diglyceride, or a diacylglycerol (DAG is a Glyceride consisting of two Fatty acid chains covalently bonded to a Glycerol Protein kinase C ('PKC') is a family of protein kinases consisting of ~10 Isozymes. Others are ceramide, the eicosanoids, and lysophosphatidic acid. Ceramides are a family of Lipid molecules A ceramide is composed of Sphingosine and a Fatty acid. In biochemistry eicosanoids are signaling molecules made by Oxygenation of twenty-carbon Essential fatty acids (EFAs Lysophosphatidic acid (LPA is a Phospholipid derivative that acts as a potent signaling molecule

Nitric oxide (NO) as second messenger - The gas nitric oxide is a free radical that diffuses through the plasma membrane and affects nearby cells. Nitric oxide or nitrogen monoxide is a Chemical compound with Chemical formula N[[Oxygen O]] In Chemistry, radicals (often referred to as free radicals) are atoms molecules or ions with Unpaired electrons on an otherwise Open shell NO is made from arginine and oxygen by the enzyme NO synthase, with citrulline as a by-product. Arginine (abbreviated as Arg or R) is an α- Amino acid. The L-form is one of the 20 most common natural amino acids Nitric oxide synthases ((NOSs are present among Eukaryotic enzymes as dimeric calmodulin-dependent or calmodulin-containing Cytochrome p450 -like Hemoprotein that The Organic compound citrulline is an α- Amino acid. Its name is derived from citrullus, the Latin word for Watermelon, from which NO works mainly through activation of its target receptor, the enzyme soluble guanylate cyclase, which, when activated, produces the second messenger cyclic-guanosine monophosphate (cGMP). NO can also act through covalent modification of proteins or their metal cofactors. Some of these modifications are reversible and work through a redox mechanism. Redox (shorthand for reduction-oxidation reaction describes all Chemical reactions in which atoms have their Oxidation number ( Oxidation state In high concentrations, NO is toxic, and is thought to be responsible for some damage after a stroke. A stroke is the rapidly developing loss of brain functions due to a disturbance in the blood vessels supplying blood to the brain NO serves multiple functions. These include:

1. Relaxation of blood vessels
2. Regulation of exocytosis of neurotransmitters
3. Cellular immune response
4. Modulation of the Hair Cycle
5. Production and maintenance of penile erections
6. Activation of apoptosis by initiating signals that lead to H2AX phosphorylation. The blood vessels are part of the Circulatory system and function to transport Blood throughout the body Exocytosis (ek-soh-sy-TOH-sis Greek: Έξω - external and κύτος - cell is the durable process by which a cell directs secretory vesicles out of the Cell See Chemical synapse for an introduction to concepts and terminology used in this article An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor Baldness involves the state of lacking hair where it often grows especially on the head The erection of the Penis, Clitoris or a Nipple is its enlarged and firm state

See also

• Functional selectivity
• G protein-coupled receptor -- GTPases -- Protein phosphatase
• MAPK/ERK pathway - a signal transduction pathway linking cell surface receptors to transcription factors
• Redox signaling

References

Further reading

Non-technical

• Cosma Shalizi's "Signal transduction" Notebook from 2003-01-20 used under the GFDL with permission
• Werner R. Loewenstein, The Touchstone of Life: Molecular Information, Cell Communication, and the Foundations of Life, Oxford University Press, 1999, ISBN 0-19-514057-5

Technical

• Gomperts, Kramer, Tatham, "Signal Transduction", AP/Elsevier [2002], ISBN 0122896319. Year 1999 ( MCMXCIX) was a Common year starting on Friday (link will display full 1999 Gregorian calendar) Reference book, for more information: http://www.cellbiol.net .
• Gerhard Krauss, Biochemistry of Signal Transduction and Regulation, Wiley-VCH, 1999, ISBN 3-527-30378-2
• John T. Year 1999 ( MCMXCIX) was a Common year starting on Friday (link will display full 1999 Gregorian calendar) Hancock, Cell Signalling, Addison-Wesley, 1998 ISBN 0-582-31267-1

External links

• Signal Transduction - The Virtual Library of Biochemistry and Cell Biology
• TRANSPATH(R) - A database about signal transduction pathways
• Science's STKE - Signal Transduction Knowledge Environment, from the journal Science, published by AAAS. Year 1998 ( MCMXCVIII) was a Common year starting on Thursday (link will display full 1998 Gregorian calendar)
• MeSH Signal+Transduction
• UCSD-Nature Signaling Gateway, from Nature Publishing Group
• LitInspector - Signal transduction pathway mining in PubMed abstracts