p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation

Brouns, Madeleine R.; Matheson, Stephen; Settleman, Jeffrey

doi:10.1038/35070042

Cited by 228 publications

(207 citation statements)

References 49 publications

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“…p190RhoGAP localizes to structures relatively poor in stress fibers [108] and arc-like structures in EGF stimulated cells with concomitant reduction in actin stress fibers [114], suggesting a functional link between the RhoGAP and actin dynamics during cell spreading and growth factor signaling [114,115]. However, while activation of p190RhoGAP requires tyrosine phosphorylation of Y1105 [116][117][118], tyrosine phosphorylation alone appears insufficient to activate p190 RhoGAP activity, at least in response to growth factor stimulation [119,120]. It is currently not known whether p190RhoGAP is regulated by ERK signaling.…”

Section: Erk Regulation Of Rho-rock Functionmentioning

confidence: 99%

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

Pullikuth

Catling

2007

Cellular Signalling

135

107

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Cell migration is critical for many physiological processes and is often misregulated in developmental disorders and pathological conditions including cancer and neurodegeneration. MAPK signaling and the Rho family of proteins are known regulators of cell migration that exert their influence on cellular cytoskeleton during cell adhesion and migration. Here we review data supporting the view that localized ERK signaling mediated through recently identified scaffold proteins may regulate cell migration.

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Section: Erk Regulation Of Rho-rock Functionmentioning

confidence: 99%

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

Pullikuth

Catling

2007

Cellular Signalling

135

107

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“…Nerve growth factor (NGF) was however, the function of these molecules in the brain has obtained from Life Technologies, (LTI, Rockville, MD, been suggested only for a few using cell culture systems USA). The rabbit polyclonal anti-ARHGAP4 antibody was [18,23,26,42,48,56] or mutant mice [7,8]. The physiologiraised against a peptide corresponding to 4-20 aa of rat cal importance of GTPase regulatory proteins in the ARHGAP4, conjugated to keyhole limpet hemocyanin and nervous system is further highlighted by the reports of affinity purified.…”

Section: Like Other Gtpases Rho Gtpases Cycle Between Activementioning

confidence: 99%

Cloning of rat ARHGAP4/C1, a RhoGAP family member expressed in the nervous system that colocalizes with the Golgi complex and microtubules

Foletta

Brown

Young

2002

Molecular Brain Research

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The Rho GTPase family of intracellular molecular switches control multiple cellular functions via the regulation of the actin cytoskeleton. Increasing evidence implicates a critical involvement of these molecules in the nervous system, particularly during neuronal migration and polarity, axon and growth cone guidance, dendritic arborization and synaptic formation. However, the molecules regulating Rho GTPase activities in the nervous system are less known. Here, we present the cloning of rat ARHGAP4, a member of the Rho GTPase activating protein family, and also demonstrate its close linkage to the vasopressin 2 receptor gene. In vitro, recombinant ARHGAP4 stimulated the GTPase activity of three members of Rho GTPases, Rac1, Cdc42 and RhoA. ARHGAP4 mRNA expression was observed in multiple tissues with marked expression throughout the developing and adult nervous systems. On closer analysis of protein levels, ARHGAP4 was significantly restricted to specific regions in the nervous system. These included the stratum lucidem in the CA3 area of the hippocampus, neuronal fibers in the ventral region of the brainstem and striatum, and in the cerebellar granule cells. Subcellularly, endogenous ARHGAP4 expression localized to the Golgi complex and could redistribute to the microtubules, for example during mitosis. In addition, distinct protein expression was observed in the tips of differentiating neurites of PC12 cells. Collectively, these results demonstrate that ARHGAP4 is more widely expressed than previously thought but potentially possesses specialized activity in regulating members of the Rho GTPase family in specific cellular compartments of the nervous system. Published by Elsevier Science B.V. Theme: Cellular and molecular biologyTopic: Gene structure and function Keywords: RhoGAP; Nervous system; Golgi network; Microtubulin; cDNA cloning; In situ hybridization histochemistry and immunofluorescence . Introductionidentified thus far, Rho, Rac and Cdc42 remain the best characterized and are increasingly being shown to mediate Rho GTPases are members of the Ras superfamily of morphological changes during neuronal development and small GTP-binding molecules that regulate diverse cellular synaptic plasticity via the actin cytoskeleton (reviewed in processes including cell movement, growth and differentia- [29]). However, neuronal expression analyses of various tion (reviewed in [54]

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“…For example, the RhoGAP domain of p190 RhoGAP can catalyze GTP hydrolysis of RhoA, RhoB, and RhoC equally well but works weakly on Rac or Cdc42 (28,29). It depends on other regulatory domains in the RhoGAP to direct and regulate substrate selection and catalysis in vivo (30,31). Conversely, although Rho proteins may share up to 90% sequence identity, each Rho subtype appears to play distinct roles in cellular transformation and metastasis.…”

mentioning

confidence: 99%

A Novel Strategy for Specifically Down-regulating Individual Rho GTPase Activity in Tumor Cells

Wang

Yang

Luo

et al. 2003

Journal of Biological Chemistry

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The Rho family GTPases RhoA, RhoB, and RhoC regulate the actin cytoskeleton, cell movement, and cell growth. Unlike Ras, up-regulation or overexpression of these GDP/GTP binding molecular switches, but not activating point mutations, has been associated with human cancer. Although they share over 85% sequence identity, RhoA, RhoB, and RhoC appear to play distinct roles in cell transformation and metastasis. In NIH 3T3 cells, RhoA or RhoB overexpression causes transformation whereas RhoC increases the cell migration rate. To specifically target RhoA, RhoB, or RhoC function, we have generated a set of chimeric molecules by fusing the RhoGAP domain of p190, a GTPase-activating protein that accelerates the intrinsic GTPase activity of all three Rho GTPases, with the C-terminal hypervariable sequences of RhoA, RhoB, or RhoC. The p190-Rho chimeras were active as GTPase-activating proteins toward RhoA in vitro, co-localized with the respective active Rho proteins, and specifically down-regulated Rho protein activities in cells depending on which Rho GTPase sequences were included in the chimeras. In particular, the p190-RhoA-C chimera specifically inhibited RhoA-induced transformation whereas p190-RhoC-C specifically reversed the migration phenotype induced by the active RhoC. In human mammary epithelial-RhoC breast cancer cells, p190-RhoC-C, but not p190-RhoA-C or p190-RhoB-C, reversed the anchorageindependent growth and invasion phenotypes caused by RhoC overexpression. In the highly metastatic A375-M human melanoma cells, p190-RhoC-C specifically reversed migration, and invasion phenotypes attributed to RhoC up-regulation. Thus, we have developed a novel strategy utilizing RhoGAP-Rho chimeras to specifically down-regulate individual Rho activity and demonstrate that this approach may be applied to multiple human tumor cells to reverse the growth and/or invasion phenotypes associated with disregulation of a distinct subtype of Rho GTPase.

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p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation

Cited by 228 publications

References 49 publications

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

Cloning of rat ARHGAP4/C1, a RhoGAP family member expressed in the nervous system that colocalizes with the Golgi complex and microtubules

A Novel Strategy for Specifically Down-regulating Individual Rho GTPase Activity in Tumor Cells

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