Pathway: RHOV GTPase cycle
Reactions in pathway: RHOV GTPase cycle :
RHOV GTPase cycle
RHOV (also known as Chp) is an atypical RHO GTPase that is thought to be constitutively active due to its high intrinsic guanine nucleotide exchange activity. No guanine nucleotide exchange factors (GEFs) nor GTPase activator proteins (GAPs) that act on RHOV have been identified. RHOV is expressed at very low levels. The expression of RHOV is detected during embryonic development in fish (Tay et al. 2010), frog (Guémar et al. 2007) and chicken (Notarnicola et al. 2008). RHOV is involved in neural crest formation, where its expression is induced downstream of WNT signaling. RHOV is thought to regulate cell adhesion, as its zebrafish orthologue is required for proper localization of E-cadherin and beta-catenin at adherens junctions. RHOV activates JNK and induces apoptosis in rat pheochromocytoma cell line PC12 (Shepelev et al 2011) and in macrophages (Song et al. 2015).
RHOV gene overexpression is a molecular marker of human lung adenocarcinoma (Shepelev and Korobko 2013, Shukla et al. 2017, Ma et al. 2020, Zhang et al. 2020), where RHOV is likely to act as an oncogene (Chen et al. 2021).
For review, please refer to Faure and Fort 2015, and Hodge and Ridley 2020.
RHOV gene overexpression is a molecular marker of human lung adenocarcinoma (Shepelev and Korobko 2013, Shukla et al. 2017, Ma et al. 2020, Zhang et al. 2020), where RHOV is likely to act as an oncogene (Chen et al. 2021).
For review, please refer to Faure and Fort 2015, and Hodge and Ridley 2020.
RAS-like proteins are small GTP binding proteins characterized structurally by 5 G boxes that are involved in nucleotide binding and hydrolysis. RAS-like proteins are typically active when bound to GTP and inactive when bound to GDP. Conversion between the two states is mediated by effector proteins: among others, GTPase activating proteins (GAPs) enable hydrolysis of bound GTP to form GDP, which remains bound, and guanine nucleotide exchange factors (GEFs) enable exchange of bound GDP for free GTP (intracellular GTP concentrations are typically an order of magnitude higher than GDP concentrations) (reviewed in Tetlow and Tamanoi, 2013).
The human genome includes over 150 members of the RAS superfamily grouped into five main subfamilies: RAS, RHO, ARF, RAB and RAN. These small GTPases affect a wide range of critical processes including gene expression, signal transduction, cell morphology, vesicle and nuclear trafficking, cellular proliferation and motility, among others (reviewed in Tetlow and Tamanoi, 2013).
The RHO family of GTPases is large and diverse, with many of its members considered to be master regulators of actin cytoskeleton, involved in the regulation of cellular processes that depend on dynamic reorganization of the cytoskeleton, including cell migration, cell adhesion, cell division, establishment of cellular polarity and intracellular transport (reviewed in Hodge and Ridley 2016, and Olson 2018).
MIRO proteins and RHOBTB3 protein, sometimes called atypical RHO proteins, show a high degree of overall sequence similarity to members of the five RAS-like subfamilies but diverge in their functions enough to constitute two separate subfamilies (Boureux et al. 2007). MIRO proteins have intrinsically high GTPase activity and do not require GTPase activator proteins (Peters et al. 2018). They play an important role mitochondrial biogenesis, maintenance and organization (reviewed in Birsa et al. 2013). The GTPase domain of RHOBTB3 is divergent from other Ras like superfamily members and displays ATPase activity (Espinosa et al. 2009). RHOBTB3 is involved in CUL3 dependent protein ubiquitination (Berthold et al. 2008; Ji and Rivero 2016), retrograde transport from endosomes to the Golgi apparatus (Espinosa et al. 2009), regulation of the cell cycle and in modulating the adaptive response to hypoxia (Ji and Rivero 2016).
The human genome includes over 150 members of the RAS superfamily grouped into five main subfamilies: RAS, RHO, ARF, RAB and RAN. These small GTPases affect a wide range of critical processes including gene expression, signal transduction, cell morphology, vesicle and nuclear trafficking, cellular proliferation and motility, among others (reviewed in Tetlow and Tamanoi, 2013).
The RHO family of GTPases is large and diverse, with many of its members considered to be master regulators of actin cytoskeleton, involved in the regulation of cellular processes that depend on dynamic reorganization of the cytoskeleton, including cell migration, cell adhesion, cell division, establishment of cellular polarity and intracellular transport (reviewed in Hodge and Ridley 2016, and Olson 2018).
MIRO proteins and RHOBTB3 protein, sometimes called atypical RHO proteins, show a high degree of overall sequence similarity to members of the five RAS-like subfamilies but diverge in their functions enough to constitute two separate subfamilies (Boureux et al. 2007). MIRO proteins have intrinsically high GTPase activity and do not require GTPase activator proteins (Peters et al. 2018). They play an important role mitochondrial biogenesis, maintenance and organization (reviewed in Birsa et al. 2013). The GTPase domain of RHOBTB3 is divergent from other Ras like superfamily members and displays ATPase activity (Espinosa et al. 2009). RHOBTB3 is involved in CUL3 dependent protein ubiquitination (Berthold et al. 2008; Ji and Rivero 2016), retrograde transport from endosomes to the Golgi apparatus (Espinosa et al. 2009), regulation of the cell cycle and in modulating the adaptive response to hypoxia (Ji and Rivero 2016).
Signal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such as hormones and growth factors, or reacting to other types of stimuli, such as light. Stimulation of transmembrane receptors leads to their conformational change which propagates the signal to the intracellular environment by activating downstream signaling cascades. Depending on the cellular context, this may impact cellular proliferation, differentiation, and survival. On the organism level, signal transduction regulates overall growth and behavior.
Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al, 2005), which ultimately results in changes in gene expression and cellular metabolism.
Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors.
WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009).
NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009).
Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) .
Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011).
Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al, 2005), which ultimately results in changes in gene expression and cellular metabolism.
Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors.
WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009).
NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009).
Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) .
Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011).