p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities

Xy, Yang; Guan, Ming; Vigil, Dominico; Der, Channing J.; Dr, Lowy; Popescu, N. C.

doi:10.1038/onc.2008.498

Cited by 61 publications

(67 citation statements)

References 47 publications

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“…It has been reported that Ras-GAP interacts with DLC1 at focal adhesions 18 . In addition, the overexpression of Ras-GAP was shown to impair the growth inhibitory activity of DLC1 and increase the RhoA level in cells, suggesting that Ras-GAP is a negative regulator of the RhoGAP activity of DLC1.…”

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confidence: 99%

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Chan

Sze

et al. 2013

Nat Commun

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Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that encodes a RhoGTPase-activating protein (RhoGAP) and is frequently inactivated in many human cancers. The RhoGAP activity of DLC1 against Rho signalling is well documented and is strongly associated with the tumour suppressor functions of DLC1. However, the mechanism by which the RhoGAP activity of DLC1 is regulated remains obscure. Here, we report that phosphorylation of DLC1 at Ser549 by cyclic AMP-dependent protein kinase A contributes to enhanced RhoGAP activity and promotes the activation of DLC1, which suppresses hepatoma cell growth, motility and metastasis in both in vitro and in vivo models. Intriguingly, we found that Ser549 phosphorylation induces the dimerization of DLC1 and that inducible dimerization of DLC1 can rescue the tumour suppressive and RhoGAP activities of DLC1 containing a Ser549 deletion. Our study establishes a novel regulatory mechanism for DLC1 RhoGAP activity via dimerization induced by protein kinase A signalling.

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confidence: 99%

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Chan

Sze

et al. 2013

Nat Commun

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“…GAP Activity-The SH3 domain of p120 has been reported as a novel binding partner of DLC1 with GAP-inhibitory and growth suppression activity (11). To monitor this effect in real time, DLC1 GAP activity was measured in the absence and presence of purified p120 SH3 under the same conditions as in the experiments described above (Fig.…”

Section: P120 Sh3 As a Potent Trans-inhibitory Factor Of The Dlc1mentioning

confidence: 99%

“…This mechanism was later revealed to involve DLC1 but not p190 (11). Here, the p120 SH3 domain (called p120 SH3 ) binds to the RhoGAP domain of DLC1 (called DLC1 GAP ) and inhibits the DLC1-dependent Rho inactivation (11). Hereby, p120 acts as a negative regulator not only for Ras but also for the GAP activity of DLC1.…”

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confidence: 99%

“…Another mechanism, which connects the Ras and Rho pathways and regulates the actin cytoskeleton, is dependent on the p120 SH3 domain and controls Rho activation (41). This mechanism was later revealed to involve DLC1 but not p190 (11). Here, the p120 SH3 domain (called p120 SH3 ) binds to the RhoGAP domain of DLC1 (called DLC1 GAP ) and inhibits the DLC1-dependent Rho inactivation (11).…”

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confidence: 99%

“…Whereas the C terminus of p120 with the catalytic GAP activity is responsible for Ras inactivation (38 -40), its N-terminal Src homology 2 and 3 (SH2 and SH3) domains have been suggested to possess an effector function (41)(42)(43)(44). p120 functionally modulates Rho signaling by direct binding to two Rho-specific GAPs, p190 and DLC1 (9,11,45). The association of p120 with the tyrosine phosphorylated p190 via its SH2 domain promotes Rho inactivation (45)(46)(47).…”

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confidence: 99%

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Functional Cross-talk between Ras and Rho Pathways

Jaiswal

Dvorský

Amin

et al. 2014

Journal of Biological Chemistry

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Background:The regulatory mechanism of the DLC1 tumor suppressor protein is unclear. Results: Structure-function analysis revealed determinants for the selectivity, activity, and inhibition of DLC1 RhoGAP function. Conclusion: p120RasGAP competitively and selectively inhibits DLC1 by targeting its catalytic arginine finger. Significance: This mechanistic study emphasizes the importance of the functional inter-relationships of GTPase-activating proteins mediating cross-talk between the Ras and Rho pathways.

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Commonality and Stochasticity in Systems Toxicology

Hirabayashi

Inoue

2009

General, Applied and Systems Toxicology

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“Systems toxicology” is “systems biology” applied to general toxicology, which is to elucidate a universal concept of biological interactions between living organisms and xenobiotics by global assays of transcriptomics, proteomics and other various applied omics studies, during various biological steps in in vivo responses, in developmental, pubertal and senescent stages, and at the ontological or phylogenical level, in addition to in vitro cellular responses. The aim of the chapter is to focus on systems toxicology to incorporate a new biological concept that distinguishes commonality and stochasticity from those xenobiotic responses when one incorporates computational toxicological data from the gene chip microarray into systems toxicology. The multiplicity of biological reactions can be better understood when common gene expression profiles and stochastic gene expression profiles would be unsupervisedly analyzed computationally. Previous toxicological data have been analysed frequently with their average endpoints focused on the commonality. However, probabilistic stochasticity may be analysed as specific stochastic clusters that elucidate other aspects of biological diversity in future “systems toxicology”.

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p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities

Cited by 61 publications

References 47 publications

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Functional Cross-talk between Ras and Rho Pathways

Commonality and Stochasticity in Systems Toxicology

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