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G12/G13-mediated signalling in mammalian physiology and disease

2008; Elsevier BV; Volume: 29; Issue: 11 Linguagem: Inglês

10.1016/j.tips.2008.08.002

1873-3735

Thomas Worzfeld, Nina Wettschureck, Stefan Offermanns,

Cell Adhesion Molecules Research

The human genome encodes hundreds of G-protein-coupled receptors. Their intracellular effects, however, are mediated by only four families of heterotrimeric G proteins: Gs, Gi/Go, Gq/G11 and G12/G13. Progress in the knowledge about the G12/G13 family has somewhat lagged behind because their downstream effectors remained unknown for several years, and tools to specifically interfere with G12/G13-mediated signalling were, therefore, missing. However, with the identification of G12/G13-regulated signalling pathways and the recent application of new techniques, such as conditional gene inactivation, RNA interference or expression of inhibitory proteins, new insights into the in vivo functions of this G-protein family have been gained. It has become clear that this pathway regulates cellular proliferation, movement and morphology in many different organs and that it is centrally involved in various diseases including cancer and cardiovascular disorders. Here, we focus on recent progress made in the analyses of the in vivo functions of mammalian G12/G13-mediated signalling. The human genome encodes hundreds of G-protein-coupled receptors. Their intracellular effects, however, are mediated by only four families of heterotrimeric G proteins: Gs, Gi/Go, Gq/G11 and G12/G13. Progress in the knowledge about the G12/G13 family has somewhat lagged behind because their downstream effectors remained unknown for several years, and tools to specifically interfere with G12/G13-mediated signalling were, therefore, missing. However, with the identification of G12/G13-regulated signalling pathways and the recent application of new techniques, such as conditional gene inactivation, RNA interference or expression of inhibitory proteins, new insights into the in vivo functions of this G-protein family have been gained. It has become clear that this pathway regulates cellular proliferation, movement and morphology in many different organs and that it is centrally involved in various diseases including cancer and cardiovascular disorders. Here, we focus on recent progress made in the analyses of the in vivo functions of mammalian G12/G13-mediated signalling. cellular polarization is a result of subcellular asymmetric compartmentalization of proteins, mRNAs or organelles and is essential for the proper function of many, if not all, cell types. a family of receptors characterized by seven transmembrane helical domains, which couple to G proteins to mediate the effects of a huge variety of ligands including hormones, growth factors, paracrine factors, neurotransmitters or sensory stimuli. guanine-nucleotide-binding proteins (G proteins) are heterotrimeric GTP-binding proteins that bind and hydrolyse the guanine nucleotide GTP. They are primarily involved in transmembrane signal transduction by coupling membraneous receptors to various effectors. specialized cellular compartments at the front of a polarized cell that are enriched in actin and various signalling molecules and are required for proper directional migration. a specialized splenic B-cell population involved in the early phase of antibody production in response to bacterial antigens. regulator of G-protein signalling (RGS) protein domains inhibit G-protein-mediated signalling by activating the GTPase activity of defined G-protein α subunits. the GTPase RhoA belongs to a large superfamily of monomeric GTP-binding proteins, which act as molecular switches by cycling between an inactive GDP-bound and an active GTP-bound state. Rho family members regulate the organization of the cytoskeleton. Rho guanine-nucleotide-exchange factor (RhoGEF) proteins are characterized by a protein domain that activates RhoA by promoting the exchange of GDP for GTP.