Cell Signalling its types and mechanism of action
Cells respond to extracellular signals produced by other cells or by themselves. This mechanism, called cell signalling, allows cell-cell communication and is necessary for the functional regulation and integration of multi-cellular organisms. We will discuss in this unit the basis for understanding normal cell function. Signalling molecules are either secreted or expressed at the cell surface of cell. Signalling molecules can bind to receptors on the surface of another cell or the same cell. Different type of signalling molecules transmit information in multi-cellular organisms, and their mechanisms of action on their cells can be diverse. Some signalling molecules can act on the cell surface after binding to cell surface receptors; others can cross the plasma membrane and bind on intracellular receptors in the cytoplasm and nucleus. When a signalling molecule binds to its receptor, it initiates a cascade of intracellular reactions to regulate critical functions such as cell proliferation, differentiation, movement, metabolism, and behaviour. Because of their critical role in the control of normal cell growth and differentiation, signalling molecules have acquired significant relevance in cancer research.
Types of Cell Signalling
Five major types of cell-cell signalling are considered:
- Endocrine cell signalling involves a signalling molecule, called a hormone, secreted by an endocrine cell and transported through the circulation to act on distant target cells. As example is the steroid hormone testosterone produced in the testes that stimulate the development and maintenance of the male reproductive tract.
- Paracrine Cell signalling is mediated by a signalling molecule acting locally to regulate the behaviour of a nearly cell. An example is the action neurotransmitters produced by nerve cells and released at a synapse.
- Autocrine cell signalling is defined by cells responding to signalling molecules that they themselves produce. A classic example is the response of cells of the immune system to foreign antigens or growth factors that trigger their own proliferation and differentiation. Abnormal autocrine signalling leads to the unregulated growth of cancer cells.
- Neurotransmitter cell signalling a specific form of paracring signalling.
- Neuroendocriner cell signalling, a specific form of endocrine signalling.
Cell signalling molecules and their mechanism of action
Cell signalling molecules exert their action after binding to receptors expressed by their target cells, can determine either a negative or positive feedback action to regulate the release of the targeting hormone. Cell receptors can be expressed on the cell surface of the target cells. Some receptors are intracellular proteins in the cytosol or the nucleus of target cells. Intracellular receptors require that the signalling molecules diffuse across the plasma membrane.
Steroid hormones belong to this class of signalling molecules. Steroid hormones are symthesized form cholesterol and include testosterone, estrogen, progesterone, and corticosteroids. Testoterone, estrogen, and progesterone are sex steroids and are produced by the gonads. Corticosteroids are produced by the cortex of the adrenal gland and include two major classes: glucocorticoids, which stimulate the production of glucose, and mineralocorticoids, which act on the kidney to regulate water and salt balance.
There are three cell signalling molecules that are structurally and functionally distinct from steroids but act on target cells by binding to intracellular receptors after entering the cell by diffusion across the plasma membrane. They include thyroid hormone (produced in the thyroid gland to regulate development and metabolism), Vitamin D (regulates calcium metabolism and bone growth), and retinoids (synthesized from vitamin A to regulate development). Steroid receptors are members of the steroid receptor super family. They act as transcription factors through their DNA binding domains, which have transcription activation or repression functions. Steroid hormones and related molecules can therefore regulate gene expression.
In the androgen insensitivity syndrome (also known as the testicular feminization syndrome [T fm]) there is a mutation in the gene expressing the testosterone receptor such that the receptor cannot bind the hormone, and hence the cells do not respond to the hormone. Although genetically male, the individual develops the secondary sexual characteristics of a female. Nitric oxide is also a signalling molecule. It is a simple gas synthesized from the amino acid arginine by the enzyme nitric oxide synthase. It acts as a paracrine signalling molecule in the nervous, immune, and circulatory systems. Like steroid hormones, nitric oxide can diffuse across the plasma membrane of its target cells. Unlike steroids, nitric oxide does not bind to an intracellular receptor to regulate transcription. Instead, it regulates the activity of intracellular target enzymes.
Nitric oxide increases the activity of the second messenger cyclic guanosine monophosphate in smooth muscle cells, which then causes cell muscle relaxation and blood vessel dilation. Nitroglycerin, a pharmacologic agent used in the treatment of heart disease, is converted to nitric oxide, which increases heart blood flow by dilation of the coronary blood vessels.
Cell Surface Receptors and their mechanism of action
When a cell signalling molecule binds to a specific receptor, it activates a series of intracellular targets located downstream of the receptor. Several molecules associated with receptors have been identified:
- G protein-coupled receptors (guanine nucleotide-binding proteins): Members of a large family of G proteins (more than 1000 proteins) are present at the inner leaflet of the plasma membrane When a signalling molecule or receptor ligand binds to the extracellular portion of a cell surface receptor, its cytosolic domain undergoes a conformational change that enables binding of the receptor to a G protein. This contact activates the G protein, which then dissociates from the receptor and triggers an intracellular signal to an enzyme or ion channel.
- Tyrosine kinases as receptor proteins: These surface receptors are themselves enzymes that phosphotylate substrate proteins on tyrosine residues. EGF, NGF, PDGF, insulin, and several growth factors are receptor protein tyrosine kinases. Most of the receptor protein tyrosine kinases consist of single polypeptides, although the insulin receptor and other growth factors consist of a pair of polypeptide chains. Binding of a ligand (a growth factor) to the extracellular domain of these receptors induces receptor dimerization that results in receptor autophosphorylation (the two polypeptide chains phosphorylate one another). The autophosphorylation of there receptors determines the binding of the tyrosine kinase domain to downstream signalling molecules. Downstream signalling molecules bind to phosphotyrosine residues through domains called SH2 domains (for Sre homology2). Sre (for sarcoma) is a gene present in the tumor-producing Rous sarcoma virus and encodes a protein that function as a protein tyrosine kinase.
- Cytokine receptors: This family of receptors stimulates intracellular protein tyrosine kinases, which are not intrinsic components of the receptor. A growth factor ligand induces the dimerization and crossphosphorylation of the associated tyrosine kinases. Activated kinases phosphorylate the receptors, providing binding sites for downstream signalling molecules that contain the SH2 domain.
- Receptors linked to other enzymes (protein tyrosine phosphatases and protein serine and threonine kinases): Some receptors associate with protein tyrosine phosphatases to remove phosphate groups from phosphotyrosine residues. Therefore, they regulate the effect of protein tyrosine kinases by arresting signals initiated by protein tyrosine phosphorylation. Members of the transforming growth factor-ß (TGF-ß) family are protein kinases that phosphorylate serine and threonine residues (rather than tyrosine). TGF-ß inhibits the proliferation of their target cells.