Cell signaling is part of a
complex systemof communicationthat governs basic cellular activities and coordinates cell actions. [Witzany, G. (2000). Life: The Communicative Structure. Norderstedt, Libri BoD.] 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 diseasessuch 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 biologyresearch helps us to understand the underlying structure of cell signaling networksand how changes in these networks may affect the transmission and flow of information. Such networks are complex systemsin their organization and may exhibit a number of emergentproperties including bistabilityand ultrasensitivity. Analysis of cell signaling networks requires a combination of experimental and theoretical approaches including the development and analysis of simulationsand modelling.
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 embryocells exchange signals with cells of the uterus.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. Entrez Pubmed|15930138.] In the human gastrointestinal tract, bacteriaexchange signals with each other and with human epithelial and immune systemcells.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. Entrez Pubmed|15890712.] For the yeast " Saccharomyces cerevisiae" during mating, some cells send a peptidesignal (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.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. Entrez Pubmed|14966283.]
Types of signals
Some cell-to-cell communication requires direct cell-cell contact. Some cells can form
gap junctions that connect their cytoplasmto the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allows for action potentialpropagation from the cardiac pacemakerregion of the heart to spread and coordinately cause contraction of the heart.
Notch signalingmechanism 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. This requirement for direct contact allows for very precise control of cell differentiationduring embryonic development. In the worm " Caenorhabditis elegans", two cells of the developing gonadeach 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 loopor 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.I. Greenwald (1998) "LIN-12/Notch signaling: lessons from worms and flies" in"Genes in Development" Volume 12, pages 1751-1762. Entrez Pubmed|9637676.]
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, epinephrineand norepinephrinecan function as hormones when released from the adrenal glandand 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.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. Entrez Pubmed|15537737.] Estrogencan be released by the ovaryand function as a hormone or act locally via paracrine or autocrinesignaling.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. Entrez Pubmed|15525594.]
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 factorsbut 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
hydrophobicmolecule that can pass through the lipid bilayerof 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.
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
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
GABAcan activate a cell surface receptor that is part of an ion channel. GABA binding to a GABA A receptoron 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 transductionmechanism 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 cycleand divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylationcan 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 kinasethat can attach phosphateto target proteins such as the transcription factorMYC 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
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.
Neurotransmittersrepresent 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
* "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.
Molecular Cellular Cognition
*MAPK signaling pathway
*Hedgehog signaling pathway
TGF beta signaling pathway
JAK-STAT signaling pathway
cAMP dependent pathway
* [http://www.signaling-gateway.org Signaling Gateway] Free summaries of recent research and the [http://www.signaling-gateway.org/molecule/ Molecule Pages database] .
* [http://pid.nci.nih.gov NCI-Nature Pathway Interaction Database] : authoritative information about signaling pathways in human cells.
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=%22Cell+signaling%22+AND+mboc4%5Bbook%5D+AND+373842%5Buid%5D&rid=mboc4.section.2743#2793 Cell Communication] , Chapter 15 in " [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=cell+biology+AND+mboc4%5Bbook%5D+AND+373693%5Buid%5D&rid=mboc4 Molecular Biology of the Cell] " fourth edition, edited by Bruce Alberts (2002) published by Garland Science.
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=%22Cell+signaling%22+AND+cooper%5Bbook%5D+AND+166039%5Buid%5D&rid=cooper.chapter.2198 Cell Signaling] , Chapter 13 in " [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=cell+biology+AND+cooper%5Bbook%5D+AND+165077%5Buid%5D&rid=cooper.chapter.89 The Cell - A Molecular Approach] " second edition, by Geoffrey M. Cooper (2000) published by Sinauer Associates.
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=%22Cell+signaling%22+AND+mcb%5Bbook%5D+AND+107116%5Buid%5D&rid=mcb.chapter.5687 Cell-to-Cell Signaling] , Chapter 20 in " [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=cell+biology+AND+mcb%5Bbook%5D+AND+105032%5Buid%5D&rid=mcb.chapter.145 Molecular Cell Biology] " fourth edition, edited by Harvey Lodish (2000) published by W. H. Freeman and Company.
* [http://www.esignet.net ESIGNET Research Project ]
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