Activation of Ras and Rho GTPases and MAP Kinases by G-Protein-Coupled Receptors
A complex intracellular signaling network mediates the multiple biological activities of G-protein-coupled receptors (GPCRs). Among them, monomeric GTPases and a family of closely related proline-targeted serine–threonine kinases, collectively known as Mi
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Introduction G-protein-coupled receptors (GPCRs) represent by far the largest family of proteins involved in signal transmission accounting for more than 2% of the total genes encoded by the human genome. These receptors control key physiological functions, including neurotransmission, hormone, and enzyme release from endocrine and exocrine glands, immune responses, cardiac- and smooth-muscle contraction, and blood pressure regulation, to name but a few. Consequently, their dysfunctions contributes Rony Seger (ed.), MAP Kinase Signaling Protocols: Second Edition, Methods in Molecular Biology, vol. 661, DOI 10.1007/978-1-60761-795-2_8, © Springer Science+Business Media, LLC 2010
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to the pathogenesis of a large number of human diseases, as reflected by the fact that GPCRs represent the target of more than 50% of the current therapeutic agents on the market. GPCRs are coupled to heterotrimeric GTPases that consist of Ga, Gb, and Gg subunits that in an inactive state are bound to GDP through the Ga subunit (1). Upon ligand binding, a conformational change in the receptor provokes Ga to release GDP and incorporate GTP. As a consequence, GTP-bound Ga and the Gbg subunits dissociate, and Ga-GTP and free Gbg initiate the activation of a multitude of effector molecules. GPCRs are best known by their ability to activate or inhibit the production of a variety of second messengers such as cAMP, cGMP, diacylglycerol, IP3, PIP3, arachidonic, and phosphatidic acid, and promoting (Ca2+) elevation and the opening or closing of a variety of ion channels (2, 3). However, cellular responses mediated by GPCRs do not involve the sole stimulation of conventional second messenger-generating systems, but also result from the functional integration of an intricate network of intracellular signaling pathways. Among others, GPCRs also induce the activation of monomeric GTPases of the Ras superfamily which, in turn, stimulate the activation of several members of a family of closely related proline-targeted serine–threonine kinases, collectively known as Mitogen-Activated Protein Kinases (MAPKs) (4). Indeed, both small GTPases such as Ras, RhoA, Rac1, and Cdc42 and MAPKs such as ERK1/2, JNKs, p38a (HOG1), p38g (ERK6), p38d (SAPK4), and ERK5 are all activated by GPCRs and control their proliferative effects (Fig. 1). Following a very complex and not fully elucidated series of events originating from stimulation of GPCRs by appropriate ligands (3), GPCRs activate small GTPases of the Ras and Rho family, which ultimately lead to the phosphorylation and activation of MAPKs on conserved tyrosine and threonine residues by their immediately upstream MAPK kinases (or MEKs) (5). Active MAPKs then can phosphorylate cytosolic targets and translocate to the nucleus. Here, MAPKs phosphorylate transcription factors, thereby regulating the expression of genes that play a key role in normal and aberrant cell growth (5). Thus, efforts to understand the basic molecular processes by which GPCRs regulate the enzymatic activity of small
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