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Overview of Receptors and Signal Transduction Pathways

Overview of Receptors and Signal Transduction Pathways

 

The binding of a ligand to its receptor triggers a series of events by which extracellular signals are transduced into the cell and modulate changes in gene expression. A common form of ligand-receptor interaction involves the dimerization or trimerization of receptor molecules; single receptor molecules can also transduce signals but usually do so after recruiting and attaching cytoplasmic adapter proteins. Receptors are generally located on the surface of the target cell but can also be found in the cytoplasm or nucleus. A receptor protein has binding specificity for particular ligands, and the resulting receptor-ligand complex may initiate specific or multiple cellular responses.

Although the field of signal transduction is vast and beyond our scope, it is useful to summarize the properties of the major types of receptors and how they deliver signals to the cell interior ( Fig. 3-9 ). This is pertinent not only to an understanding of normal cell growth, but also for the understanding of the molecular basis of cancer ( Chapter 7 ).

Figure 3-9  Examples of signal transduction systems that require cell-surface receptors. Shown are receptors with intrinsic tyrosine kinase activity, seven transmembrane G-protein-coupled receptors, and receptors without intrinsic tyrosine kinase activity. The figure also shows important signaling pathways transduced by the activation of these receptors through ligand binding.

  

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Receptors with intrinsic tyrosine kinase activity. The ligands for receptors with tyrosine kinase activity include most growth factors such as EGF (epidermal growth factor), TGF-α (transforming growth factor-α), HGF (hepatocyte growth factor/scatter factor), PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), c-KIT ligand, and insulin. Receptors belonging to this family have an extracellular ligand-binding domain, a transmembrane region, and a cytoplasmic tail that has intrinsic tyrosine kinase activity. Binding of the ligand induces dimerization of the receptor, tyrosine phosphorylation, and activation of the receptor tyrosine kinase[52][53]( Fig. 3-10 ). The active kinase then phosphorylates, and thereby activates, many downstream effector molecules (molecules that mediate the effects of receptor engagement with a ligand). Phosphorylated residues in the receptor also serve as docking sites for adapter molecules that bind effector molecules. Effector molecules include phospholipase Cγ(PLCγ) and PI-3 kinase ( Fig. 3-9 ).[54] PLCγ catalyzes the breakdown of membrane inositol phospholipids into two products—inositol triphosphate (IP3), which functions to increase concentrations of another important effector molecule, calcium; and diacylglycerol, which activates the serine-threonine kinase protein kinase C (PKC), which in turn activates various transcription factors. PI-3 kinase phosphorylates a membrane phospholipid, generating products that activate the kinase Akt (also referred to as protein kinase B). Akt is involved in cell proliferation and in inhibition of apoptosis and is a key intermediate in the insulin signal transduction pathway mediated by PI-3K[55] (see Chapter 24 ). As mentioned above, phosphorylated residues in the receptor also function as docking sites for adapter proteins that are capable of binding other effector proteins. A prototypical adapter protein is GRB-2, which binds a GTP:GDP exchange factor called SOS. SOS acts on the GTP-binding (G) protein RAS and catalyzes the formation of RAS-GTP, which triggers the mitogen-activated protein kinase (MAP kinase) cascade (see Fig. 3-10 ). Active MAP kinases stimulate the synthesis and phosphorylation of transcription factors, such as FOS and JUN. The transcription factors activated by these various signaling cascades in turn stimulate the production of growth factors, receptors for growth factors, and proteins that directly control the entry of cells into the cell cycle.[56] Defects in receptor tyrosine kinase pathways are found in many human diseases, including cancer ( Chapter 7 ), type 2 diabetes ( Chapter 25 ), and atherosclerosis ( Chapter 11 ).

  

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Receptors lacking intrinsic tyrosine kinase activity that recruit kinases. Ligands for these receptors include many cytokines, such as interleukin-2 (IL-2), IL-3, and other interleukins; interferons α, β, and γ; erythropoietin; granulocyte colony-stimulating factor; growth hormone; and prolactin. These receptors transmit extracellular signals to the nucleus by activating members of the JAK (Janus kinase) family of proteins ( Fig. 3-9 ).[57] The JAKs link the receptors with and activate cytoplasmic transcription factors called STATs (signal transducers and activation of transcription), which directly shuttle into the nucleus and activate gene transcription.[58] Cytokine receptors can also activate other signaling pathways, such as the MAP kinase pathways already mentioned.

  

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Seven transmembrane G-protein-coupled receptors (GPCRs). These receptors were so named because they contain seven transmembrane α-helices ( Fig. 3-9 ).[59] They constitute the largest family of plasma membrane receptors (more than 1500 receptors of this class have been identified) and transmit signals into the cell through trimeric GTP-binding proteins (G-proteins). A large number of ligands signal through this type of receptor.[60] They include vasopressin, serotonin, histamine, epinephrine and norepinephrine, calcitonin, glucagon, parathyroid hormone, corticotropin, rhodopsin, and an enormous number of common pharmaceutical drugs. Binding of the ligand induces changes in the conformation of the receptors, causing their activation and allowing their interaction with many different G-proteins. Activation of G-proteins occurs by the exchange of GDP, present in the inactive protein, with GTP, in the active protein. Among the many branches of this signal transduction pathway are those involving calcium and adenosine 3', 5'-cyclic monophosphate (cAMP) as second messengers.[61] Activation of seven transmembrane G-protein-coupled receptors (as well as of tyrosine kinase receptors, discussed above) can produce inositol 1,4,5-triphosphate (IP3), which releases calcium from the endoplasmic reticulum. Calcium signals, which are generally oscillatory, have a multiplicity of targets, including cytoskeletal proteins, chloride- and potassium-activated ion pumps, enzymes such as calpain, and calcium-binding proteins such as calmodulin.[62] cAMP activates a more restricted set of targets that include protein kinase A and cAMP-gated ion channels, important in vision and olfactory sensing. Defects involving GPCR signal transduction include retinitis pigmentosa, corticotropin deficiencies, and hyperparathyroidism.[63]

  

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Steroid hormone receptors. The ligands for these receptors diffuse through the cell membrane and bind to receptors located in the nucleus or less frequently in the cytoplasm. Receptors of this family are transcription factors that bind a ligand and activate transcription.[64] The estrogen receptor, important in breast cancers, is localized in the cytoplasm.[65] In addition to steroid hormones, other ligands that bind to members of this receptor family include thyroid hormone, vitamin D, and retinoids. A group of receptors belonging to this family are called peroxisome proliferator-activated receptors (PPARs).[66] They are involved in a broad range of responses that include cell differentiation and adipogenesis ( Chapter 24 ).

 

Figure 3-10  Signaling from tyrosine kinase receptors. Binding of the growth factor (ligand) causes receptor dimerization and autophosphorylation of tyrosine residues. Attachment of adapter (or bridging) proteins (e.g., GRB2 and SOS) couples the receptor to inactive RAS. Cycling of RAS between its inactive and active forms is regulated by GAP. Activated RAS interacts with and activates RAF (also known as MAP kinase kinase kinase). This kinase then phosphorylates a component of the MAP kinase signaling pathway, MEK (also known as MAP kinase kinase), which then phosphorylates ERK (MAP kinase). Activated MAP kinase phosphorylates other cytoplasmic proteins and nuclear transcription factors, generating cellular responses. The phosphorylated tyrosine kinase receptor can also bind other components, such as PI-3 kinase, which activates distinct signaling systems.

(From: http://www.mdconsult.com/das/book/body/106862079-3/756980818/1249/32.html#4-u1.0-B0-7216-0187-1..50007-9--cesec21_214)

 



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