AbstractsBiology & Animal Science

Involvement of the Microtubule-Regulated RhoGEF GEF-H1 in the G12 family signaling pathways

by Georgina Garrido Antequera

Institution: Universitat de Barcelona
Year: 2014
Keywords: Proteïnes G; Proteínas G; G Proteins; Homeòstasi; Homeostasis; Citocinesi; Citocinesis; Cytokinesis; Ciències Experimentals i Matemàtiques
Record ID: 1126762
Full text PDF: http://hdl.handle.net/10803/283979


Heterotrimeric G proteins are masters regulators of cell homeostasis. They coordinate the signaling between G protein coupled receptors (GPCRs) and their intracellular effectors. Heterotrimeric G proteins are composed of three subunits: G-alpha, G-beta, G-gamma. They function as a switches between an inactive GDP-bound state and an active GTP•bound state. Upon receptor activation, the G-alpha subunit undergoes a conformational change that leads to the exchange of GTP for GDP and the dissociation of the G-alpha subunit from the G-beta-gammadimer, allowing the subunits to activate their downstream effectors. The signal is terminated when the G-alpha subunit hydrolyzes its bound GTP to GDP and re-associates with G-beta-gamma. There are four subfamilies of G proteins: G-alpha (i), G-alpha(q), G-alpha(s) and G-alpha(12). Each subfamily can activate a different subset of effectors and signaling pathways. The subfamily of the G-alpha(12) protein is composed of two members: G-alpha(12) and G-alpha(13). They are involved in different processes such as embryonic development, cell growth, cell migration, angiogenesis processes and apoptosis. G-alpha(12) and G-alpha(13) have been linked to cellular events such as cytoskeletal rearrangements and cell proliferation through the activation of the small GTPase RhoA and moreover, they activate Rho principally through direct interaction with Rho-specific guanine nucleotide exchange factors (RhoGEFs). A growing number of RhoGEFs have recently been identified, with a majority as a members of the Dbl family of RhoGEF proteins. This proteins share in common a DH domain, the catalytic domain, and a PH domain, a pleckstrin homology domain. There are four RhoGEFs to be directly stimulated by the G-alpha(12/13) subfamily: p115RhoGEF, LARG, PDZRhoGEF and AKAP-Lbc. Three of them form the RH-RhoGEF subfamily because they share in common a RGS homology domain which is the implicated in their interaction with G12 proteins. GEF-Hl was discovered as a microtubule associated protein and belongs to the AKAP-Lbc subfamily. It has been reported to be regulated by its binding to microtubules, while microtubule-bound GEF-Hl is associated to have low activity its release from them leads to GEF-Hl activation and consequently, the activation of the small RhoGTPase RhoA. GEF-Hl can also be regulated by phosphorylation and several kinases can phosphorylate GEF-Hl in different moments of the cell. For instance, during cytokinesis GEF-Hl is phosphorylated by Aurora kinases and Cdk/Cyclin 8 in order to regulate its activity towars RhoA, due to be a high controlled spatiotemporal process. GEF-Hl is also considered a key player in the cross-talk of microtubules to actin dynamics and is reported to be involved in a variety of normal biological situations such as cell cycle regulation, and cell morphology, polarity and motility. Conventionally G proteins have been linked with the plasma membrane where they exert their functions. However, several studies during the last years have shown that Gproteins can also…