RhoG

RhoG ( R as ho mology G rowth-related) (or ARGH) is a small (~21 is_associated_with::kDa) monomeric GTP-binding is_associated_with::protein (is_associated_with::G protein), and is an important component of many is_associated_with::intracellular is_associated_with::signalling pathways. It is a member of the Rac subfamily of the is_associated_with::Rho family of small is_associated_with::G proteins and is encoded by the is_associated_with::gene RHOG.

Discovery
RhoG was first identified as a is_associated_with::coding sequence upregulated in hamster lung is_associated_with::fibroblasts upon stimulation with serum. Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts, is_associated_with::leukocytes, is_associated_with::neuronal cells, is_associated_with::endothelial cells and is_associated_with::HeLa cells. RhoG belongs to the Rac subgroup and emerged as a consequence of retroposition in early vertebrates. RhoG shares a subset of common binding partners with Rac, Cdc42 and RhoU/V members but a major specificity is its inability to bind to CRIB domain proteins such as PAKs.

Function
Like most small G proteins RhoG is involved in a diverse set of is_associated_with::cellular signalling mechanisms. In mammalian cells these include is_associated_with::cell motility (through regulation of the is_associated_with::actin is_associated_with::cytoskeleton), is_associated_with::gene transcription, is_associated_with::endocytosis, is_associated_with::neurite outgrowth, protection from is_associated_with::anoikis and regulation of the is_associated_with::neutrophil is_associated_with::NADPH oxidase.

Regulation of RhoG activity
As with all small G proteins RhoG is able to signal to downstream effectors when bound to GTP (is_associated_with::Guanosine triphosphate) and unable to signal when bound to GDP (is_associated_with::Guanosine diphosphate). Three classes of protein interact with RhoG to regulate GTP/GDP loading. The first are known as is_associated_with::Guanine nucleotide exchange factors (GEFs) and these facilitate the exchange of GDP for GTP so as to promote subsequent RhoG-mediated signalling. The second class are known as is_associated_with::GTPase activating proteins (GAPs) and these promote is_associated_with::hydrolysis of GTP to GDP (via the intrinsic is_associated_with::GTPase activity of the G protein) thus terminating RhoG-mediated signalling. A third group, known as is_associated_with::Guanine nucleotide dissociation inhibitors (GDIs), inhibit dissociation of GDP and thus lock the G protein in its inactive state. GDIs can also sequester G proteins in the is_associated_with::cytosol which also prevents their activation. The dynamic regulation of G protein signalling is necessarily complex and the 130 or more GEFs, GAPs and GDIs described thus far for the Rho family are considered to be the primary determinants of their spatiotemporal activity.

There are a number of GEFs reported to interact with RhoG, although in some cases the physiological significance of these interactions has yet to be proven. Well characterised examples include the dual specificity GEF TRIO which is able to promote nucleotide exchange on RhoG and Rac (via its GEFD1 domain) and also on is_associated_with::RhoA via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF-induced neurite outgrowth in is_associated_with::PC12 cells and is_associated_with::phagocytosis of is_associated_with::apoptotic cells in C. elegans. Another GEF, known as is_associated_with::SGEF ( S rc homology 3 domain-containing G uanine nucleotide E xchange F actor), is thought to be RhoG-specific and has been reported to stimulate is_associated_with::macropinocytosis (internalisation of is_associated_with::extracellular fluid) in fibroblasts and apical cup assembly in endothelial cells (an important stage in leukocyte trans-endothelial migration). Other GEFs reported to interact with RhoG include Dbs, is_associated_with::ECT2, is_associated_with::VAV2 and is_associated_with::VAV3.

There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include is_associated_with::IQGAP2 and RhoGDI3.

Signalling downstream of RhoG
Activated G proteins are able to couple to multiple downstream effectors and can therefore control a number of distinct signalling pathways (a characteristic known as is_associated_with::pleiotropy). The extent to which RhoG regulates these pathways is poorly understood thus far, however, one specific pathway downstream of RhoG has received much attention and is therefore well characterised. This pathway involves RhoG-dependent activation of Rac via the DOCK ( d edicator o f c yto k inesis)-family of GEFs. This family is divided into four subfamilies (A-D) and it is subfamilies A and B that are involved in the pathway described here. is_associated_with::Dock180, the archetypal member of this family, is seen as an atypical GEF in that efficient GEF activity requires the presence of the DOCK-binding protein ELMO ( e ngulfment and cel l mo tility) which binds RhoG at its is_associated_with::N-terminus. The proposed model for RhoG-dependent Rac activation involves recruitment of the of ELMO/Dock180 complex to activated RhoG at the is_associated_with::plasma membrane and this relocalisation, together with an ELMO-dependent conformational change in Dock180, is sufficient to promote GTP-loading of Rac. RhoG-mediated Rac signalling has been shown to promote neurite outgrowth and cell migration in mammalian cells as well as phagocytosis of apoptotic cells in C. elegans.

Other proteins known to bind RhoG in its GTP-bound state include the is_associated_with::microtubule-associated protein kinectin, is_associated_with::Phospholipase D1 and the is_associated_with::MAP Kinase activator is_associated_with::MLK3.

Interactions
RhoG has been shown to interact with is_associated_with::KTN1.