RhoG
Encyclopedia
RhoG (or ARGH) is a small (~21 kDa
) monomeric GTP
-binding protein
(G protein
), and is an important component of many intracellular
signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene
RHOG.
. Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts, leukocytes, neuronal cells, endothelial cells and 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.
mechanisms. In mammalian cells these include cell motility (through regulation of the actin
cytoskeleton
), gene transcription, endocytosis
, neurite
outgrowth, protection from anoikis
and regulation of the neutrophil NADPH oxidase
.
) and unable to signal when bound to GDP (Guanosine diphosphate
).
Three classes of protein interact with RhoG to regulate GTP/GDP loading. The first are known as 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 GTPase activating protein
s (GAPs) and these promote hydrolysis
of GTP to GDP (via the intrinsic GTPase
activity of the G protein) thus terminating RhoG-mediated signalling. A third group, known as 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 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 RhoA
via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF
-induced neurite outgrowth in PC12 cells
and phagocytosis of apoptotic cells in C. elegans
. Another GEF, known as SGEF
(Src homology 3 domain-containing Guanine nucleotide Exchange Factor), is thought to be RhoG-specific and has been reported to stimulate macropinocytosis (internalisation of 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, ECT2
, VAV2
and VAV3
.
There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include IQGAP2
and RhoGDI3
.
). 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 (dedicator of cytokinesis)-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. 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
(engulfment and cell motility) which binds RhoG at its N-terminus. The proposed model for RhoG-dependent Rac activation involves recruitment of the of ELMO/Dock180 complex to activated RhoG at the 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 microtubule
-associated protein kinectin
, Phospholipase D1
and the MAP Kinase activator MLK3.
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
) monomeric GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
-binding protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
(G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
), and is an important component of many intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
RHOG.
Discovery
RhoG was first identified as a coding sequence upregulated in hamster lung fibroblasts upon stimulation with serumBlood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
. Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts, leukocytes, neuronal cells, endothelial cells and 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 cellular signallingCellular Signalling
Cellular Signalling is a peer-reviewed scientific journal focusing on various aspects of cell signalling.- Abstracting and indexing :Cellular Signalling is abstracted and indexed in:...
mechanisms. In mammalian cells these include cell motility (through regulation of the actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
), gene transcription, endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
outgrowth, protection from anoikis
Anoikis
Anoikis is a form of programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix . Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide...
and regulation of the neutrophil NADPH oxidase
NADPH oxidase
The NADPH oxidase is a membrane-bound enzyme complex. It can be found in the plasma membrane as well as in the membrane of phagosome.-Subunits:It is made up of six subunits...
.
Regulation of RhoG activity
As with all small G proteins RhoG is able to signal to downstream effectors when bound to GTP (Guanosine triphosphateGuanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
) and unable to signal when bound to GDP (Guanosine diphosphate
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
).
Three classes of protein interact with RhoG to regulate GTP/GDP loading. The first are known as 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 GTPase activating protein
GTPase activating protein
GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event...
s (GAPs) and these promote hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of GTP to GDP (via the intrinsic GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
activity of the G protein) thus terminating RhoG-mediated signalling. A third group, known as 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 cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
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
TRIO (gene)
Triple functional domain protein is a protein that in humans is encoded by the TRIO gene.-Interactions:TRIO has been shown to interact with Filamin and RHOA.-Further reading:...
which is able to promote nucleotide exchange on RhoG and Rac (via its GEFD1 domain) and also on RhoA
RHOA
Ras homolog gene family, member A is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. In humans, it is encoded by the gene RHOA....
via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
-induced neurite outgrowth in PC12 cells
PC12 cells
PC12 is a cell line derived from a pheochromocytoma of the rat adrenal medulla. PC12 cells stop dividing and terminally differentiate when treated with nerve growth factor...
and phagocytosis of apoptotic cells in C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
. Another GEF, known as SGEF
SGEF
SGEF is a 97 kDa protein involved in intracellular signalling networks. It functions as a guanine nucleotide exchange factor for RhoG, a small G protein of the Rho family.-Discovery:...
(Src homology 3 domain-containing Guanine nucleotide Exchange Factor), is thought to be RhoG-specific and has been reported to stimulate macropinocytosis (internalisation of extracellular fluid
Extracellular fluid
Extracellular fluid usually denotes all body fluid outside of cells. The remainder is called intracellular fluid.In some animals, including mammals, the extracellular fluid can be divided into two major subcompartments, interstitial fluid and blood plasma...
) in fibroblasts and apical cup assembly in endothelial cells (an important stage in leukocyte trans-endothelial migration
Leukocyte extravasation
Leukocyte extravasation is the movement of leukocytes out of the circulatory system, towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes...
). Other GEFs reported to interact with RhoG include Dbs, ECT2
ECT2
Protein ECT2 is a protein that in humans is encoded by the ECT2 gene.-Further reading:...
, VAV2
VAV2
Guanine nucleotide exchange factor VAV2 is a protein that in humans is encoded by the VAV2 gene.-Interactions:VAV2 has been shown to interact with CD19 and Grb2.-Further reading:...
and VAV3
VAV3
Guanine nucleotide exchange factor VAV3 is a protein that in humans is encoded by the VAV3 gene.-Further reading:...
.
There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include IQGAP2
IQGAP2
Ras GTPase-activating-like protein IQGAP2 is an enzyme that in humans is encoded by the IQGAP2 gene.-Interactions:IQGAP2 has been shown to interact with CDC42 and RAC1.-Further reading:...
and RhoGDI3
ARHGDIG
Rho GDP-dissociation inhibitor 3 is a protein that in humans is encoded by the ARHGDIG gene.-Further reading:...
.
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 pleiotropyPleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...
). 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
RAC
-Companies:* Rent-A-Center, an American public furniture and electronics rent to own company* Royal Automobile Club, a private club in Pall Mall, London* RAC plc, a breakdown company in the United Kingdom...
via the DOCK (dedicator of cytokinesis)-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. 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
ELMO (protein)
ELMO is a family of related proteins involved in intracellular signalling networks. These proteins have no intrinsic catalytic activity and instead function as adaptors which can regulate the activity of other proteins through their ability to mediate protein-protein interactions.This family...
(engulfment and cell motility) which binds RhoG at its N-terminus. The proposed model for RhoG-dependent Rac activation involves recruitment of the of ELMO/Dock180 complex to activated RhoG at the 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 microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
-associated protein kinectin
KTN1
Kinectin is a protein that in humans is encoded by the KTN1 gene.-Interactions:KTN1 has been shown to interact with EEF1D, RhoG and RHOA.-Further reading:...
, Phospholipase D1
Phospholipase D1
Phospholipase D1 is an enzyme that in humans is encoded by the PLD1 gene.-Interactions:Phospholipase D1 has been shown to interact with RALA, BIN1, Amphiphysin, Alpha-synuclein, PEA15, RHOA, Protein kinase N1 and CDC42.-Inhibitors:...
and the MAP Kinase activator MLK3.