A complex community of cells.

Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. This article describes complex system as a type of system For other meanings see Complex systems. Communication is the process of conveying information from a sender to a receiver with the use of a medium in which the communicated information is understood the same way ^[1] The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Immunity is a material term that describes a state of having sufficient biological defenses to avoid Infection, Disease, or other unwanted biological invasion Homeostasis (from Greek: ὅμος hómos, "equal" and ιστημι istēmi, "to stand" lit Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. A disease is an abnormal condition of an organism that impairs bodily functions and can be deadly Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled 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 Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc By understanding cell signaling, diseases may be treated effectively and, theoretically, artificial tissues may be yielded.

Traditional work in biology has focused on studying individual parts of cell signaling pathways. Systems biology research helps us to understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and flow of information. Systems biology is a biology-based inter-disciplinary study field that focuses on the systematic study of complex interactions in biological systems, thus using a new perspective Such networks are complex systems in their organization and may exhibit a number of emergent properties including bistability and ultrasensitivity. This article describes complex systems as field of Science. For other meanings see Complex system. Something that is bistable can be resting in two states In physics for an ensemble of particles the bistability comes from the fact that its free energy Analysis of cell signaling networks requires a combination of experimental and theoretical approaches including the development and analysis of simulations and modelling. Simulation is the imitation of some real thing state of affairs or process The Movement for Democracy in Liberia (MODEL was a rebel group in Liberia that became active in March 2003, launching attacks from Côte d'Ivoire.

Unicellular and multicellular organism cell signaling

Figure 1. Example of signaling between bacteria. Salmonella enteritidis uses acyl-homoserine lactone for Quorum sensing (see: Inter-Bacterial Communication)

Cell signaling has been most extensively studied in the context of human diseases and signaling between cells of a single organism. Salmonella enterica is a rod shaped Flagellated Gram-negative Bacterium, and a member of the Genus Salmonella Homoserine lactones are signaling Chemicals involved in microbiological Quorum sensing. Quorum sensing is a type of decision-making process used by decentralized groups to coordinate behavior A disease is an abnormal condition of an organism that impairs bodily functions and can be deadly However, cell signaling may also occur between the cells of two different organisms. In many mammals, early embryo cells exchange signals with cells of the uterus. Mammals ( class Mammalia) are a class of Vertebrate Animals characterized by the presence of Sweat glands, including sweat glands An embryo (from Greek:, plural, lit "that which grows" from en- "in" + bryein "to swell be full" is a multicellular The uterus (from the Latin word for womb) is the major Female reproductive organ of most Mammals including Humans One end the ^[2] In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have In biology and medicine epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout the body An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor ^[3] For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. Saccharomyces cerevisiae is a Species of Budding Yeast. It is perhaps the most useful Yeast owing to its use since ancient times The yeast Saccharomyces cerevisiae is a simple single celled Eukaryote with both a Diploid and Haploid mode of existence Peptides (from the Greek πεπτίδια, "small digestibles" are short Polymers formed from the linking in a defined order of α- Amino A pheromone (from Greek φέρω phero "to bear" + ‘ορμόνη " Hormone " is a Chemical that triggers a natural The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating. In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling ^[4]

Types of signals

Figure 2. Notch-mediated juxtacrine signal between adjacent cells.

Some cell-to-cell communication requires direct cell-cell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. A gap junction or nexus is a specialized Intercellular connection between certain animal cell -types The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. In cardiac muscle, gap junctions between adjacent cells allows for action potential propagation from the cardiac pacemaker region of the heart to spread and coordinately cause contraction of the heart. The cardiac muscle is a type of involuntary striated Muscle found in the walls of the Heart. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal The contractions of the Heart are controlled by chemical impulses which fire at a rate which controls the beat of the heart

The Notch signaling mechanism is an example of juxtacrine signalling (also known as contact dependent signaling) in which two adjacent cells must make physical contact in order to communicate. In biology juxtacrine signaling is a type of Intercellular communication which is transmitted via Oligosaccharide, Lipid or Protein components This requirement for direct contact allows for very precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. Caenorhabditis elegans (ˌsiːnoʊræbˈdaɪtɪs ˈɛlɪgænz is a free-living Nematode (roundworm about 1  mm in length which The gonad is the organ that makes Gametes The gonads in males are the Testes and the gonads in Females are the Ovaries. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and increases Notch on the surface of the cell that continues as a stem cell. Feedback is a circular causal Process whereby some proportion of a system's output is returned (fed back to the Input. Stem cells are cells found in most if not all multi-cellular Organisms. ^[5]

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrine signals are called hormones. The endocrine system is an integrated system of small organs that involve the release of extracellular signaling molecules known as Hormones The endocrine system is instrumental Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. This is an article about the rock music band "Circulatory System" Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals target only cells in the vicinity of the emitting cell. Paracrine signaling is a form of Cell signaling in which the target cell is near (" Para " = near the signal-releasing cell Neurotransmitters represent an example. See Chemical synapse for an introduction to concepts and terminology used in this article Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a In Mammals the adrenal glands (also known as suprarenal glands) are the triangle-shaped Endocrine glands that sit on top of the Kidneys their Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information ^[6] Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling. Estrogens (US otherwise oestrogens or œstrogens) are a group of Steroid compounds named for their importance in the Estrous cycle, "Ovaria" redirects here This is also a proposed section and a Synonym of Solanum. Autocrine signaling is a form of signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent that binds to autocrine receptors on the same cell leading ^[7]

Receptors for cell signals

Cells receive information from their environment through a class of proteins known as receptors. In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, growth factors but all of these are called receptor ligands. Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body See Chemical synapse for an introduction to concepts and terminology used in this article Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule The details of ligand-receptor interactions are fundamental to cell signaling.

As shown in Figure 2 (above, left), Notch acts as a receptor for ligands that are expressed on adjacent cells. While many receptors are cell surface proteins, some are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of cell surface membranes. In Chemistry, hydrophobicity (from the combining form of water in Attic Greek hydro- and for fear phobos) refers to the physical property of A lipid bilayer or bilayer lipid membrane ( BLM) is a membrane composed of Lipid molecules (usually Phospholipids. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Estrogen receptors inside cells of the uterus can be activated by estrogen that comes from the ovaries, enters the target cells, and binds to estrogen receptors. The estrogen receptor (ER is a member of the nuclear hormone family of Intracellular receptors which is activated by the Hormone 17β-estradiol

Other signaling molecules are unable to permeate the hydrophobic cell membrane due to their hydrophilic nature, so their target receptor is expressed on the membrane. When such signaling molecule activates its receptor, the signal is carried into the cell usually by means of a second messenger such as cAMP.

Signaling pathways

Figure 3. Diagram showing key components of a signal transduction pathway. See the MAPK/ERK pathway article for details. The MAPK/ERK pathway is a Signal transduction pathway that couples intracellular responses to the binding of Growth factors to cell surface receptors

In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. Gamma-aminobutyric acid (GABA is the chief inhibitory Neurotransmitter in the Mammalian Central nervous system. Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living GABA binding to a GABA A receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. The GABAA receptor is one of two ligand-gated Ion channels responsible for mediating the effects of Gamma-aminobutyric acid (GABA the major The chloride Ion is formed when the element Chlorine picks up one Electron to form an Anion (negatively-charged ion Cl&minus GABA A receptor activation allows negatively charged chloride ions to move into the neuron which inhibits the ability of the neuron to produce action potentials. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. Physiology (from Greek grc φύσις physis, "nature origin" and grc -λογία -logia) is the study of the mechanical physical Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway. In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another

In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2 (above, left), activation of Notch can cause the Notch protein to be altered by a protease. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link Part of the Notch protein is released from the cell surface membrane and can act to change the pattern of gene transcription in the cell nucleus. Transcription is the synthesis of RNA under the direction of DNA In Cell biology, the nucleus (pl nuclei; from Latin la ''nucleus'' or la ''nuculeus'' "little nut" or kernel is a membrane-enclosed This causes the responding cell to make different proteins, resulting in an altered pattern of cell behavior. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types.

A more complex signal transduction pathway is shown in Figure 3. This pathway involves changes of protein-protein interactions inside the cell induced by an external signal. Protein-protein interactions refer to the association of Protein molecules and the study of these associations from the perspective of Biochemistry, Signal transduction Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. The cell cycle, or cell-division cycle, is the series of events that take place in a eukaryotic cell leading to its replication Cell division is a process by which a cell, called the parent cell divides into two or more cells called daughter cells. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. In Chemistry and Biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of Enzyme that transfers Phosphate This phosphorylation can generate a binding site for a different protein and thus induce protein-protein interaction. Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule Protein-protein interactions refer to the association of Protein molecules and the study of these associations from the perspective of Biochemistry, Signal transduction In Figure 3, the ligand (called epidermal growth factor (EGF)) binds to the receptor (called EGFR). Epidermal growth factor or EGF is a Growth factor that plays an important role in the regulation of Cell growth, Proliferation, and This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2) which couples the signal to further downstream signaling processes. An adaptor protein is a Protein which is accessory to main proteins in a Signal transduction pathway For example, one of the signal transduction pathways that is activated is called the mitogen-activated protein kinase (MAPK) pathway. Mitogen-activated protein (MAP kinases ( are Serine/threonine-specific protein kinases that respond to extracellular stimuli ( Mitogens and regulate various cellular The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK" so the pathway is called the MAPK/ERK pathway. The MAPK/ERK pathway is a Signal transduction pathway that couples intracellular responses to the binding of Growth factors to cell surface receptors The MAPK protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor MYC and thus alter gene transcription and, ultimately, cell cycle progression. A protein kinase is a Kinase Enzyme that modifies other Proteins by chemically adding Phosphate groups to them ( Phosphorylation) A phosphate, an Inorganic chemical, is a salt of Phosphoric acid. 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 Myc (cMyc is a gene that regulates other genes It codes for a protein that binds to the DNA of other genes Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway.

Some signaling transduction pathways respond differently depending on the amount of signaling received by the cell. For instance the hedgehog protein activates different genes depending on the amount of hedgehog protein present. In a growing embryo cells develop differently in the head or tail end of the embryo the left or right and other positions

Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.

Classification of intercellular communication

Main article: Endocrine system#Types of signaling

Within endocrinology (the study of intercellular signalling in animals) and the endocrine system, intercellular signalling is subdivided into the following classifications:

• Endocrine signals are produced by endocrine cells and travel through the blood to reach all parts of the body. The endocrine system is an integrated system of small organs that involve the release of extracellular signaling molecules known as Hormones The endocrine system is instrumental Endocrinology (from Greek grc ἔνδον endon, "within" grc κρῑνω krīnō, "to separate" and grc -λογία The endocrine system is an integrated system of small organs that involve the release of extracellular signaling molecules known as Hormones The endocrine system is instrumental The endocrine system is an integrated system of small organs that involve the release of extracellular signaling molecules known as Hormones The endocrine system is instrumental This is an article about the rock music band "Circulatory System"
• Paracrine signals target only cells in the vicinity of the emitting cell. Paracrine signaling is a form of Cell signaling in which the target cell is near (" Para " = near the signal-releasing cell Neurotransmitters represent an example. See Chemical synapse for an introduction to concepts and terminology used in this article
• Autocrine signals affect only cells that are of the same cell type as the emitting cell. Autocrine signaling is a form of signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent that binds to autocrine receptors on the same cell leading An example for autocrine signals is found in immune cells.
• Juxtacrine signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent. In biology juxtacrine signaling is a type of Intercellular communication which is transmitted via Oligosaccharide, Lipid or Protein components

See also

• Molecular Cellular Cognition
• Crosstalk (biology)
• MAPK signaling pathway
• Hedgehog signaling pathway
• TGF beta signaling pathway
• JAK-STAT signaling pathway
• cAMP dependent pathway
• Signal transduction
• Systems biology
• Semiotics

References

External links

• Signaling Gateway Free summaries of recent research and the Molecule Pages database.
• NCI-Nature Pathway Interaction Database: authoritative information about signaling pathways in human cells.
• Cell Communication, Chapter 15 in Molecular Biology of the Cell fourth edition, edited by Bruce Alberts (2002) published by Garland Science.
• Cell Signaling, Chapter 13 in The Cell - A Molecular Approach second edition, by Geoffrey M. Cooper (2000) published by Sinauer Associates.
• Cell-to-Cell Signaling, Chapter 20 in Molecular Cell Biology fourth edition, edited by Harvey Lodish (2000) published by W. H. Freeman and Company.
• MeSH Intercellular+Signaling+Peptides+and+Proteins
• MeSH Cell+Communication
• ESIGNET Research Project