Disease relevance of RHOD

• Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation [1].
• Translocation of PHAKT-GFP is inhibited by toxin-B from Clostridium difficile, indicating that it requires activity of one or more Rho guanosine triphosphatases [2].
• Cofilin was phosphorylated in N1E-115 neuroblastoma cells during lysophosphatidic acid-induced, Rho-mediated neurite retraction [3].
• Caenorhabditis elegans LET-502 is related to Rho-binding kinases and human myotonic dystrophy kinase and interacts genetically with a homolog of the regulatory subunit of smooth muscle myosin phosphatase to affect cell shape [4].
• Here, we discuss the Salmonella actin-binding proteins and how they might function in combination with entry effectors that stimulate Rho GTPases [5].

Psychiatry related information on RHOD

• We demonstrate that presynaptic changes in Rho activity at Caenorhabditis elegans neuromuscular junctions can radically change animal behavior via modulation of two separate pathways [6].
• Ras family therapy: Rab, Rho and Ral talk to the exocyst [7].
• Our results are consistent with the hypothesis that activation of GSK-3 occurs in the Rho pathway and may represent an important link between microtubules and microfilaments dynamics during neuritogenesis and in pathological situations such as Alzheimer's disease [8].
• In support of this, there is good evidence that alterations in signaling pathways involving the Rho family of small GTPases, key regulators of the actin and microtubule cytoskeletons, contribute to both syndromic and nonsyndromic mental retardation disorders [9].
• For example, recent findings have suggested a role of Rho/Rho-kinase in the regulation of cavernosal tone, and that Rho-kinase antagonism could be a new potential principle for the treatment of erectile dysfunction [10].

High impact information on RHOD

• There is also emerging evidence of the control of phospholipase D and Rho proteins by soluble tyrosine kinases and novel serine/threonine kinases [11].
• Focusing on Rho and Rac, we will discuss how their effectors regulate the actin cytoskeleton [12].
• We will describe how the activity of Rho proteins is regulated downstream from growth factor receptors and cell adhesion molecules by guanine nucleotide exchange factors and GTPase activating proteins [12].
• The Rho GTPase appears to play a crucial role in this decision of cellular fate, promoting myogenesis and inhibiting adipogenesis [13].
• Our study illustrates a molecular pathway from Wnt/Fz signaling to Rho activation in cell polarity signal transduction [14].

Chemical compound and disease context of RHOD

• Pretreatment of ganglion cell axons with C3-transferase, a specific inhibitor of the Rho GTPase, or with Y-27632, a specific inhibitor of the Rho kinase, strongly reduced the collapse rate of retinal growth cones [15].
• The stimulation of 70-kD fragment binding by nanomolar S1P, like stimulation of binding by LPA or nocodazole, was blocked by inactivation of Rho with C3 exotoxin but not by pertussis toxin-mediated inactivation of Gi [16].
• Treatment of ovarian cancer cells with alendronate resulted in inactivation of Rho, changes of cell morphology, loss of stress fiber formation, and focal adhesion assembly, and the suppression of phosphorylation of myosin light chain and tyrosine phosphorylation of focal adhesion proteins, which are essential processes for cell migration [17].
• These results suggest that alendronate inhibits Rho activation by preventing geranylgeranylation, which results in inhibition of LPA-induced migration of human ovarian cancer cells [17].
• To identify the signaling pathway to ARF and Rho activation by fMLP, we used pertussis toxin and wortmannin to examine the requirement for heterotrimeric G proteins of the Gi family and for phosphoinositide 3-kinase, respectively [18].

Biological context of RHOD

• Our results define a novel signal transduction pathway, in which hDia2C and c-Src are sequentially activated by RhoD to regulate the motility of early endosomes through interactions with the actin cytoskeleton [19].
• Assignment of the human RhoHP1 gene (ARHD) to chromosome 11q14.3 by radiation hybrid mapping [20].
• Here we report that in human cells and during Xenopus embryogenesis, Wnt/Fz signaling activates the small GTPase Rho, a key regulator of cytoskeleton architecture [14].
• Small G proteins of the Rho family, which includes Rho, Rac and Cdc42Hs, regulate phosphorylation pathways that control a range of biological functions including cytoskeleton formation and cell proliferation [21].
• The Rho-family GTP-hydrolysing proteins (GTPases), Cdc42, Rac and Rho, act as molecular switches in signalling pathways that regulate cytoskeletal architecture, gene expression and progression of the cell cycle [22].

Anatomical context of RHOD

• Here, we identify a novel splice variant of human Diaphanous, hDia2C, which specifically binds to RhoD and is recruited onto early endosomes [19].
• Thus, this deamidation of glutamine 63 by CNF1 leads to the constitutive activation of Rho, and induces the reorganization of actin stress fibres [23].
• The assembly of focal adhesions is regulated by the GTP-binding protein Rho [24].
• Studies in different areas such as cell migration, mitosis, and asymmetric cell division have shown that Ran, Rho, and heterotrimeric G proteins regulate many aspects of microtubule functions [25].
• In contrast to these well established effects of Rho and Rac on plasma membrane morphology and bulk pinocytosis, there has been no evidence for their involvement in the regulation of receptor-mediated endocytosis in clathrin-coated pits [26].

Associations of RHOD with chemical compounds

• RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase [19].
• Studies with Ras and Rho have elucidated the mechanism of GAP action by showing that their catalytic machinery is both stabilized by GAP binding and complemented by the insertion of a so-called 'arginine finger' into the phosphate-binding pocket [27].
• The inhibitory activity of GDI derives both from an ability to bind the carboxy-terminal isoprene of Rho family members and extract them from membranes, and from inhibition of GTPase cycling between the GTP- and GDP-bound states [28].
• Here we show that CNF1 catalyses the deamidation of a glutamine residue at position 63 of Rho, turning it into glutamic acid, which inhibits both intrinsic GTP hydrolysis and that stimulated by its GTPase-activating protein (GAP) [23].
• This phosphorylation was sensitive to Y-27632, a specific inhibitor of the Rho-associated kinase ROCK [3].

Physical interactions of RHOD

• Here we show that, of a large number of GTPases tested, only Rnd1 and RhoD bind the cytoplasmic domain of Plexin-A1 [29].

Other interactions of RHOD

• The underlying molecular basis for these effects of Rho proteins are incompletely understood, but in the case of Cdc42 it appears that it can drive vesicle movement through Arp2/3 complex-mediated actin polymerization at the surface of the vesicle [30].
• Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse [29].

Analytical, diagnostic and therapeutic context of RHOD

• Sequence analysis based on the structure suggests that the ACC finger fold is widespread in Rho effector proteins [31].
• PKN, a fatty acid- and Rho-activated serine/threonine kinase having a catalytic domain highly homologous to protein kinase C (PKC), was cleaved at specific sites in apoptotic Jurkat and U937 cells on Fas ligation and treatment with staurosporin or etoposide, respectively [32].
• We evaluated whether FBP17 and members of the Rho family interact in vivo with a yeast two-hybrid assay [33].
• Microinjection studies indicate that podosome assembly and polarization require concerted action of Cdc42, Rac, and Rho, thereby providing a link between sequential protrusive and adhesive activity [34].
• Coculture of monocytes with endothelial cells led to Rho activation and phosphorylation of TJ proteins [35].

References