Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
Synonyms and keywords: Cell signaling pathways
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. 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. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. 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.
Unicellular and multicellular organism cell signaling
Cell signaling has been most extensively studied in the context of human diseases and signaling between cells of a single organism. 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. In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.
Types of signals
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. 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 Notch signaling mechanism is an example of juxtacrine signalling in which two adjacent cells must make physical contact in order to communicate. 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. 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.
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. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. 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. Neurotransmitters represent an example. 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 can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.
Receptors for cell signals
Cells receive information from their environment through a class of proteins known as receptors. 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. 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. 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. 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.
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. GABA binding to a GABA A receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. 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. 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. 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 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. 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. 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. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce protein-protein interaction. In Figure 3, the ligand (called epidermal growth factor (EGF)) binds to the receptor (called EGFR). 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. For example, one of the signal transduction pathways that is activated is called the mitogen-activated protein kinase (MAPK) pathway. 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 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. 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.
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
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.
- Paracrine signals target only cells in the vicinity of the emitting cell. Neurotransmitters represent an example.
- Autocrine signals affect only cells that are of the same cell type as the emitting cell. 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.
- ↑ O. A. Mohamed, M. Jonnaert, C. Labelle-Dumais, K. Kuroda, H. J. Clarke and D. Dufort (2005) "Uterine Wnt/beta-catenin signaling is required for implantation" in Proceedings of the National Academy of Sciences of the United States of America Volume 102, pages 8579-8584. Template:Entrez Pubmed.
- ↑ M.B. Clarke and V. Sperandio (2005) "Events at the host-microbial interface of the gastrointestinal tract III. Cell-to-cell signaling among microbial flora, host, and pathogens: there is a whole lot of talking going on" in American journal of physiology. Gastrointestinal and liver physiology. Volume 288, pages G1105-9. Template:Entrez Pubmed.
- ↑ J. C. Lin, K. Duell and J. B. Konopka (2004) "A microdomain formed by the extracellular ends of the transmembrane domains promotes activation of the G protein-coupled alpha-factor receptor" in Molecular Cell Biology Volume 24, pages 2041-2051. Template:Entrez Pubmed.
- ↑ I. Greenwald (1998) "LIN-12/Notch signaling: lessons from worms and flies" in Genes in Development Volume 12, pages 1751-1762. Template:Entrez Pubmed.
- ↑ M. C. Cartford, A. Samec, M. Fister and P. C. Bickford (2004) "Cerebellar norepinephrine modulates learning of delay classical eyeblink conditioning: evidence for post-synaptic signaling via PKA" in Learning & memory Volume 11, pages 732-737. Template:Entrez Pubmed.
- ↑ S. Jesmin, C. N. Mowa, I. Sakuma, N. Matsuda, H. Togashi, M. Yoshioka, Y. Hattori and A. Kitabatake (2004) "Aromatase is abundantly expressed by neonatal rat penis but downregulated in adulthood" in Journal of Molecular Endocrinology Volume 33, pages 343-359. Template:Entrez Pubmed.
- 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.
- Intercellular+Signaling+Peptides+and+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
- Cell+Communication at the US National Library of Medicine Medical Subject Headings (MeSH)
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