Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration

Binamé, Fabien; Bidaud-Meynard, Aurélien; Magnan, Laure; Piquet, Léo; Montibus, Bertille; Chabadel, Anne; Saltel, Frédéric; Lagrée, Valérie; Moreau, Violaine

doi:10.1083/jcb.201601063

Cited by 26 publications

(50 citation statements)

References 60 publications

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“…This binding is mediated by a region of p190ARhoGAP termed the polarization localization sequence, which appears to have an autoinhibitory effect on p190ARhoGAP function. The mechanism through which this autoinhibition is overcome is unclear but, intriguingly, cancer-associated mutations in this region were shown to affect p190ARhoGAP activity and localization, and to impair the directionality of migrating cells ( Binamé et al, 2016 ). Binding of the Rho GTPases RND3 and RAC1 to a similar region has also been implicated in the regulation of the related RhoGAP ARHGAP5 (p190BRhoGAP; Wennerberg et al, 2003 ; Bustos et al, 2008 ).…”

Section: Gap Complexesmentioning

confidence: 99%

Rho GTPase signaling complexes in cell migration and invasion

Lawson

Ridley

2017

Journal of Cell Biology

413

349

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Section: Gap Complexesmentioning

confidence: 99%

Rho GTPase signaling complexes in cell migration and invasion

Lawson

Ridley

2017

Journal of Cell Biology

413

349

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“…Hence, there is good rationale for suspecting a role for p190A in invasion and metastasis. However, opposing conclusions have been reached in studies examining how p190A modulates motile capacities of oncogenically transformed cells [ 29 – 32 ]. It is well-established that p190A is essential for cell polarity and directional migration [ 11 , 33 ], but it remains to be shown if perturbation of these functions confers advantages in the context of cancer.…”

Section: Introductionmentioning

confidence: 99%

p190A RhoGAP induces CDH1 expression and cooperates with E-cadherin to activate LATS kinases and suppress tumor cell growth

et al. 2020

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The ARHGAP35 gene encoding p190A RhoGAP (p190A) is significantly altered by both mutation and allelic deletion in human cancer, but the functional implications of such alterations are not known. Here, we demonstrate for the first time that p190A is a tumor suppressor using a xenograft mouse model with carcinoma cells harboring defined ARHGAP35 alterations. In vitro, restoration of p190A expression in carcinoma cells promotes contact inhibition of proliferation (CIP) through activation of LATS kinases and phosphorylation of the proto-oncogenic transcriptional co-activator YAP. In contrast, p190A forms harboring recurrent cancer mutations exhibit loss of function in modulating the Hippo pathway, inducing CIP, as well as attenuated suppression of tumor growth in mice. We determine that p190A promotes mesenchymal to epithelial transition (MET) and elicits expression of a cassette of epithelial adherens junction-associated genes in a cell density-dependent manner. This cassette includes CDH1 encoding E-cadherin, which amplifies p190A-mediated LATS activation and is necessary for CIP. Oppositely, we establish that p190A is obligatory for E-cadherin to activate LATS kinases and induce CIP. Collectively, this work defines a novel mechanism by which p190A and E-cadherin cooperate in modulating Hippo signaling to suppress tumor cell growth.

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“…This raises the exciting possibility that pG1–pG2 is important for full p190RhoGAP activity. This observation may be due to biological effects such as differences in p190RhoGAP localization, as it has recently been suggested that regions near pG1–pG2 drive p190RhoGAP localization to membrane protrusions 11 . Additionally, reported binding partners of p190RhoGAP such as Rnd3 may bind the pG1–pG2 region and affect p190RhoGAP activity 12 .…”

Section: Resultsmentioning

confidence: 99%

p190RhoGAP proteins contain pseudoGTPase domains

Stiegler

Boggon

2017

Nat Commun

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The two p190RhoGAP proteins, p190RhoGAP-A and -B, are key regulators of Rho GTPase signaling and are essential for actin cytoskeletal structure and contractility. Here we report the discovery of two evolutionarily conserved GTPase-like domains located in the ‘middle domain’, previously thought to be unstructured. Deletion of these domains reduces RhoGAP activity. Crystal structures, MANT-GTPγS binding, thermal denaturation, biochemical assays and sequence homology analysis all strongly support defects in nucleotide-binding activity. Analysis of p190RhoGAP proteins therefore indicates the presence of two previously unidentified domains which represent an emerging group of pseudoenzymes, the pseudoGTPases.

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Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration

Cited by 26 publications

References 60 publications

Rho GTPase signaling complexes in cell migration and invasion

Rho GTPase signaling complexes in cell migration and invasion

p190A RhoGAP induces CDH1 expression and cooperates with E-cadherin to activate LATS kinases and suppress tumor cell growth

p190RhoGAP proteins contain pseudoGTPase domains

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