Involvement of the microtubule-regulated RhoGEF GEF-H1 in the G12 family signaling pathways

Abstract

Signaling via G protein-coupled receptors has been implicated in a myriad of physiological and pathological processes. The objectives of our research are directed towards the understanding of the mechanisms involved in the processes regulating cell migration and invasion via G proteins and GPCRs. The Ga12 and Ga13 comprise one of the families of the heterotrimeric G proteins and are known for their regulation of actin cytoskeleton and epithelial cell junctions, and have recently been implicated in the progression of tumor cell and cancer metastasis. These studies suggest that drugs targeting the G12 proteins may provide effective therapies for slowing the invasion of cancer. Nevertheless the regulation by agonist-activated receptors and the identity of effectors through which its actions are exerted and their mechanism of action on tumor progression are still open questions. The most extensively characterized downstream mediators of signaling through the G12 subfamily are members of the RhoA family of monomeric GTPases. The members of this family of proteins are known mainly for their role in regulating the actin cytoskeleton, but they also play important roles in dictating cell polarity, microtubule dynamics, membrane transport pathways, transcription factor activity, and cell growth. In addition, these proteins play pivotal roles in tumorigenesis and cancer progression. Ga12 and Ga13 stimulate Rho activity principally through direct interaction with RhoGEFs. GEF-H1 is a novel member of the Dbl family of guanine nucleotide exchange factors (GEFs) with RhoA-specfic enzymatic activity. Subcellular localization analysis demonstrated that GEF-H1 is associated with microtubules and its depolymerization leads to GEF-H1 activation, accompained by a RhoA-dependent reorganization of the actin cytoskeleton. Numerous pathophysiological conditions result in changes in the integrity of the microtubule cytoskeleton and in Rho activity; such changes include epithelial cell and endothelial cell dysfunction, infectious disease, and cardiac hypertrophy. GEF-H1 activity is also associated with tumorigenesis, particularly in leukemias and in cancers associated with mutated p53 tumor suppressor gene. Recently unpublished results of our group show that GEF-H1 can be regulated by Ga12.