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Cell signaling

Cell signaling

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A complex community of cells.

Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions.[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. Errors in cellular information processing are responsible fordiseases such as cancerautoimmunity, 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 signalingnetworks and how changes in these networks may affect the transmission and flow of information. Such networks are complex systems in their organization and may exhibit a number of emergent properties including bistability and ultrasensitivity. Analysis of cell signaling networks requires a combination of experimental and theoretical approaches including the development and analysis of simulations and modelling.



[edit]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. 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.[2] In the human gastrointestinal tractbacteria exchange signals with each other and with human epithelial and immune system cells.[3] For the yeast Saccharomyces cerevisiaeduring 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.[4]

[edit]Types of signals

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

Cells communicate with each other via direct contact (juxtacrine signaling), over short distances (paracrine signaling), or over large distances and/or scales (endocrine signaling).

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 (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 celldifferentiation 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.[5]

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrinesignals 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 theadrenal 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.[6] Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.[7]

[edit]Receptors for cell signals

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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 hormonesneurotransmitterscytokinesgrowth 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 thelipid bilayer of cell surface membranesEstrogen 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.

A number of transmembrane receptors[8][9] for molecules that include peptide hormones[10] and of intracellular receptors for steroid hormones exist, giving to a cell the ability to respond to a great number of hormonal and pharmacological stimuli. In diseases, often, proteins that interact with receptors are aberrantly activated, resulting in constitutively activated downstream signals[11].

For several types of intercellular signaling molecules that are unable to permeate the hydrophobic cell membrane due to their hydrophilic nature, the 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[12][13].

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[edit]Signaling pathways

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Overview of signal transduction pathways.
Figure 3. Diagram showing key components of a signal transduction pathway. See the MAPK/ERK pathway article for details.

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 produceaction 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 ultimatephysiological 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 thecell 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 are 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 thetranscription 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.

[edit]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 inimmune 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.

[edit]See also


  1. ^ Witzany, G.111 (2000). Life: The Communicative Structure. Norderstedt, Libri BoD.
  2. ^ Mohamed OA, Jonnaert M, Labelle-Dumais C, Kuroda K, Clarke HJ, Dufort D (June 2005). "Uterine Wnt/beta-catenin signaling is required for implantation". Proc. Natl. Acad. Sci. U.S.A. 102 (24): 8579–84. doi:10.1073/pnas.0500612102PMID 15930138PMC1150820.
  3. ^ Clarke MB, Sperandio V (June 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". Am. J. Physiol. Gastrointest. Liver Physiol. 288 (6): G1105–9.doi:10.1152/ajpgi.00572.2004PMID 15890712.
  4. ^ Lin JC, Duell K, Konopka JB (March 2004). "A microdomain formed by the extracellular ends of the transmembrane domains promotes activation of the G protein-coupled alpha-factor receptor". Mol. Cell. Biol. 24 (5): 2041–51. PMID 14966283PMC350546.
  5. ^ Greenwald I (June 1998). "LIN-12/Notch signaling: lessons from worms and flies". Genes Dev. 12 (12): 1751–62. PMID 9637676.
  6. ^ Cartford MC, Samec A, Fister M, Bickford PC (2004). "Cerebellar norepinephrine modulates learning of delay classical eyeblink conditioning: evidence for post-synaptic signaling via PKA". Learn. Mem. 11 (6): 732–7. doi:10.1101/lm.83104PMID 15537737PMC534701.
  7. ^ Jesmin S, Mowa CN, Sakuma I, et al. (October 2004). "Aromatase is abundantly expressed by neonatal rat penis but downregulated in adulthood".J. Mol. Endocrinol. 33 (2): 343–59. doi:10.1677/jme.1.01548PMID 15525594.
  8. ^ Domazet I, Holleran BJ, Martin SS, Lavigne P, Leduc R, Escher E, Guillemette G. The second transmembrane domain of the human type 1 angiotensin II receptor participates in the formation of the ligand binding pocket and undergoes integral pivoting movement during the process of receptor activation. J Biol Chem. 2009 May 1;284(18):11922-9. Epub 2009 Mar 9.PMID: 19276075
  9. ^ Hislop JN, Henry AG, Marchese A, von Zastrow M. Ubiquitination Regulates Proteolytic Processing of G Protein-coupled Receptors after Their Sorting to Lysosomes. J Biol Chem. 2009 Jul 17;284(29):19361-70. Epub 2009 May 11. PMID: 19433584
  10. ^ Meng H, Zhang X, Hankenson KD, Wang MM. Thrombospondin 2 potentiates notch3/jagged1 signaling. J Biol Chem. 2009 Mar 20;284(12):7866-74. Epub 2009 Jan 15. PMID: 19147503
  11. ^ Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA. Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? Bioessays. 2009 Jun;31(6):629-41. Review. PMID: 19382224
  12. ^ Goh SL, Looi Y, Shen H, Fang J, Bodner C, Houle M, Ng AC, Screaton RA, Featherstone M. Transcriptional Activation by MEIS1A in Response to Protein Kinase A Signaling Requires the Transducers of Regulated CREB Family of CREB Co-activators. J Biol Chem. 2009 Jul 10;284(28):18904-12. Epub 2009 May 27. PMID: 19473990
  13. ^ Wojtal KA, Hoekstra D, van Ijzendoorn SC. cAMP-dependent protein kinase A and the dynamics of epithelial cell surface domains: moving membranes to keep in shape. Bioessays. 2008 Feb;30(2):146-55. Review. PMID: 18200529

[edit]External links

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Cell signaling
Key concepts
Signaling pathways