Adhesion-Dependent Regulation of p190RhoGAP in the Developing Brain by the Abl-Related Gene Tyrosine Kinase

Hernández, Samuel E.; Settleman, Jeffrey; Koleske, Anthony J.

doi:10.1016/j.cub.2004.03.062

Cited by 98 publications

(114 citation statements)

References 18 publications

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“…Furthermore, different tyrosine kinases can also phosphorylate and activate another effector of RhoA, p190RhoGAP (11). This protein can be coupled to the adherens junctional complex through its association with p120-catenin (35).…”

Section: Discussionmentioning

confidence: 99%

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Castaño

Solanas

Casagolda

et al. 2007

Molecular and Cellular Biology

114

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p120-catenin is an adherens junction-associated protein that controls E-cadherin function and stability. p120-catenin also binds intracellular proteins, such as the small GTPase RhoA. In this paper, we identify the p120-catenin N-terminal regulatory domain as the docking site for RhoA. Moreover, we demonstrate that the binding of RhoA to p120-catenin is tightly controlled by the Src family-dependent phosphorylation of p120-catenin on tyrosine residues. The phosphorylation induced by Src and Fyn tyrosine kinases on p120-catenin induces opposite effects on RhoA binding. Fyn, by phosphorylating a residue located in the regulatory domain of p120-catenin (Tyr112), inhibits the interaction of this protein with RhoA. By contrast, the phosphorylation of Tyr217 and Tyr228 by Src promotes a better affinity of p120-catenin towards RhoA. In agreement with these biochemical data, results obtained in cell lines support the important role of these phosphorylation sites in the regulation of RhoA activity by p120-catenin. Taken together, these observations uncover a new regulatory mechanism acting on p120-catenin that contributes to the fine-tuned regulation of the RhoA pathways during specific signaling events.E-cadherin function is controlled posttranslationally by a family of proteins, named catenins, that bind to its cytosolic tail. Two members of this family, p120-catenin and ␤-catenin, interact at different sites of the E-cadherin molecule and are engaged in distinct functions. Whereas ␤-catenin is required for recruiting the actin cytoskeleton, p120-catenin is necessary for the stabilization of E-cadherin at the cell membrane (3). As a consequence, E-cadherin is rapidly internalized and degraded in the absence of p120-catenin (7, 13). Consequently, p120-catenin ablation in vivo causes E-cadherin deficiency, leading to severe defects in adhesion, cell polarity, and epithelial morphogenesis (7).Besides this role in regulating E-cadherin stability, p120-catenin interacts with other proteins involved in the modulation of cell-to-cell contacts. For instance, p120-catenin associates with Fer and Fyn tyrosine kinases (16,27,36). These kinases specifically phosphorylate ␤-catenin in Tyr142 (27), a modification that promotes release of ␤-catenin from the adherens junctional complex and transport to the nucleus (2, 27). Moreover, p120-catenin can interact with the Yes tyrosine kinase (27) and with a number of phosphotyrosine (PTyr) phosphatases, such as PTP (39), DEP1 (12), and SHP-1 (14, 21). These multiple associations suggest a role for p120-catenin as a scaffold protein for enzymes regulating events such as the stability of the adherens junctional complex (29).p120-catenin modulates the activity of other cellular factors. Similarly to ␤-catenin, it can be detected in the nucleus (34), where it interacts with the transcriptional factor Kaiso (6). Studies performed with Xenopus laevis have demonstrated that association of p120-catenin relieves the repression caused by Kaiso on Wnt signaling (17,25).Several results indicate that p...

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Section: Discussionmentioning

confidence: 99%

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Castaño

Solanas

Casagolda

et al. 2007

Molecular and Cellular Biology

114

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“…Arg phosphorylates and activates the Rho inhibitor p190RhoGAP after integrin-mediated adhesion (Hernandez et al, 2004b;Bradley et al, 2006). We monitored FA and stress fiber structure in p190rhogapaϪ/Ϫ (p190Ϫ/Ϫ) and littermate control p190rhogapa ϩ/ϩ (p190 ϩ/ϩ ) fibroblasts expressing YFP or Arg-YFP (Figure 4, C-F).…”

Section: Arg Kinase Activity Acts Through P190rhogap To Inhibit Rho Amentioning

confidence: 99%

“…We previously identified the 190-kDa GTPase-activating protein for Rho (p190RhoGAP) as a major Arg substrate in the developing brain (Hernandez et al, 2004b). Integrin receptor engagement induces Arg-dependent phosphorylation of p190RhoGAP (Hernandez et al, 2004b), which triggers p190RhoGAP localization to the cell membrane where it inhibits Rho activity (Bradley et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Integrin receptor engagement induces Arg-dependent phosphorylation of p190RhoGAP (Hernandez et al, 2004b), which triggers p190RhoGAP localization to the cell membrane where it inhibits Rho activity (Bradley et al, 2006). These findings led us to examine a possible role for integrin signaling through Arg, p190RhoGAP, and Rho in regulating cell adhesion and contractility during cell migration.…”

Section: Introductionmentioning

confidence: 99%

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The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin

Peacock

Miller

Bradley

et al. 2007

MBoC

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In migrating cells, actin polymerization promotes protrusion of the leading edge, whereas actomyosin contractility powers net cell body translocation. Although they promote F-actin-dependent protrusions of the cell periphery upon adhesion to fibronectin (FN), Abl family kinases inhibit cell migration on FN. We provide evidence here that the Abl-related gene (Arg/Abl2) kinase inhibits fibroblast migration by attenuating actomyosin contractility and regulating focal adhesion dynamics. arg؊/؊ fibroblasts migrate at faster average speeds than wild-type (wt) cells, whereas Arg re-expression in these cells slows migration. Surprisingly, the faster migrating arg؊/؊ fibroblasts have more prominent F-actin stress fibers and focal adhesions and exhibit increased actomyosin contractility relative to wt cells. Interestingly, Arg requires distinct functional domains to inhibit focal adhesions and actomyosin contractility. The kinase domain-containing Arg N-terminal half can act through the RhoA inhibitor p190RhoGAP to attenuate stress fiber formation and cell contractility. However, Arg requires both its kinase activity and its cytoskeleton-binding C-terminal half to fully inhibit focal adhesions. Although focal adhesions do not turn over efficiently in the trailing edge of arg؊/؊ cells, the increased contractility of arg؊/؊ cells tears the adhesions from the substrate, allowing for the faster migration observed in these cells. Together, our data strongly suggest that Arg inhibits cell migration by restricting actomyosin contractility and regulating its coupling to the substrate through focal adhesions.

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“…The Abl kinases regulate a variety of cytoskeletal processes downstream of receptor tyrosine kinases and integrins (9)(10)(11)(12)(13)(14). We have shown that Abl kinases play a role in the regulation of intercellular signals at the neuromuscular junction (NMJ) and at sites of contact between invading bacterial pathogens and mammalian host cells (9,15).…”

mentioning

confidence: 99%

Abl tyrosine kinases regulate cell–cell adhesion through Rho GTPases

Zandy

Playford

Pendergast

2007

Proc. Natl. Acad. Sci. U.S.A.

121

132

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Adhesion-Dependent Regulation of p190RhoGAP in the Developing Brain by the Abl-Related Gene Tyrosine Kinase

Cited by 98 publications

References 18 publications

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin

Abl tyrosine kinases regulate cell–cell adhesion through Rho GTPases

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