A FAK-p120RasGAP-p190RhoGAP complex regulates polarity in migrating cells

Tomar, Alok; Lim, Ssang-Taek; Lim, Yeunhwan; Schlaepfer, David D.

doi:10.1242/jcs.046870

Cited by 123 publications

(139 citation statements)

References 56 publications

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“…This suggests that although CLEC14A is localized at cellto-cell contacts, it may be poised to have a sensing role at the leading edge. It is well established that the Golgi apparatus orientates toward the direction of cell movement (Tomar et al, 2009). Staining of the Golgi with the marker GM130 showed that CLEC14A polarizes to the HUVEC leading edge (Figure 4c), providing further evidence for a role for this protein in environmental sensing and cell migration.…”

Section: Cellular Localization Of Clec14a In Endothelial Cellsmentioning

confidence: 67%

Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

et al. 2011

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Section: Cellular Localization Of Clec14a In Endothelial Cellsmentioning

confidence: 67%

Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

et al. 2011

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“…DLC1 is thought to serve as a tumor suppressor protein by antagonizing the oncogenic activity of Rho proteins in liver cancer (Wong et al, 2005;Xue et al, 2008). In contrast, p190A RhoGAP-deficient fibroblasts showed a defect in polarized cell migration (Tomar et al, 2009) although they did not exhibit any obvious defects in adhesion on extracellular matrix (Jiang et al, 2008). In both cases, the GAP activity of DLC1 and p190A was implicated in the regulation of cell migration.…”

Section: Discussionmentioning

confidence: 99%

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Northey

Primeau

et al. 2010

Oncogene

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RhoA, Rac1 and Cdc42, the best-characterized members of the Rho family of small GTPases, are critical regulators of many cellular activities. Cdc42 GTPaseactivating protein (CdGAP) is a serine-and proline-rich RhoGAP protein showing GAP activity against both Cdc42 and Rac1 but not RhoA. CdGAP is phosphorylated downstream of the MEK-ERK (extracellular signalregulated kinase) pathway in response to serum and is required for normal cell spreading and polarized lamellipodia formation. In this study, we found that CdGAP protein and mRNA levels are highly increased in mammary tumor explants expressing an activated Neu/ ErbB-2 (Neu-NT) receptor. In response to transforming growth factor-b (TGFb) stimulation, Neu-NT-expressing mammary tumor explants demonstrate a clear induction in cell motility and invasion. We show that downregulation of CdGAP expression by small interfering RNA abrogates the ability of TGFb to induce cell motility and invasion of Neu-NT-expressing mammary tumor explants. However, it has no effect on TGFb-mediated cell adhesion on type 1 collagen and fibronectin. Interestingly, protein expression of E-Cadherin is highly increased in Neu-NT-expressing mammary tumor explants depleted of CdGAP. In addition, complete loss of E-Cadherin expression is not observed in CdGAP-depleted cells during TGFb-mediated epithelial to mesenchymal transition. Downregulation of the CdGAP expression also decreases cell proliferation of Neu-NT-expressing mammary tumor explants independently of TGFb. Rescue analysis using re-expression of various CdGAP deletion-mutant proteins revealed that the proline-rich domain (PRD) but not the GAP domain of CdGAP is essential to mediate TGFbinduced cell motility and invasion. Finally, we found that TGFb induces the expression and phosphorylation of CdGAP in mammary epithelial NMuMG cells. Taken together, these studies identify CdGAP as a novel molecular target in TGFb signaling and implicate CdGAP as an essential component in the synergistic interaction between TGFb and Neu/ErbB-2 signaling pathways in breast cancer cells.

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“…Previous studies have demonstrated a critical role for FAK as a regulator of adhesion dynamics (4 -7). In addition, FAK has been shown to mediate the tyrosine phosphorylation of p190RhoGAP as a negative regulator of Rho activity in focal adhesion turnover and polarity (5,8). Furthermore, microtubule-induced focal adhesion disassembly requires FAK and dynamin (9).…”

mentioning

confidence: 99%

Regulation of Adhesion Dynamics by Calpain-mediated Proteolysis of Focal Adhesion Kinase (FAK)

Chan

Bennin

Huttenlocher

2010

Journal of Biological Chemistry

181

165

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The coordinated and dynamic regulation of adhesions is required for cell migration. We demonstrated previously that limited proteolysis of talin1 by the calcium-dependent protease calpain 2 plays a critical role in adhesion disassembly in fibroblasts ( The coordinated and dynamic regulation of adhesions is central for cell migration in both normal and pathological processes (1). Cell migration is initiated by forming protrusions, which are stabilized by integrin-mediated adhesions that establish structural and signaling linkages between the extracellular matrix and the actin cytoskeleton. Subsequently, actomyosin contractility drives forward propulsion, and finally, adhesions are disassembled to allow for directional movement. Thus, it is not surprising that efficient cell migration necessitates precise spatial and temporal control of these events. However, the mechanisms governing the formation and disassembly of adhesions are still not well understood.A prominent component involved in this regulation is focal adhesion kinase (FAK).2 FAK promotes cell migration by its capacity to orchestrate signals between integrin and growth factor receptors (2). Downstream of integrin or growth factor stimulation, FAK is phosphorylated at Tyr-397, which is an important binding site for Src family kinases (3). Previous studies have demonstrated a critical role for FAK as a regulator of adhesion dynamics (4 -7). In addition, FAK has been shown to mediate the tyrosine phosphorylation of p190RhoGAP as a negative regulator of Rho activity in focal adhesion turnover and polarity (5, 8). Furthermore, microtubule-induced focal adhesion disassembly requires FAK and dynamin (9). Nevertheless, the mechanisms by which FAK regulates the disassembly of focal adhesions remain to be elucidated. Evidence has emerged supporting the role of the calpain family of intracellular calcium-dependent proteases in regulating cell migration (10 -14). Calpains have been proposed to regulate migration, at least in part, through their ability to modulate the dynamics of adhesions (15). Numerous calpain targets have been identified, some of which are proteins that are present in focal adhesions, including talin, paxillin, and FAK (16). Thus, it is likely that proteolysis of these substrates contributes to the regulation of adhesion dynamics and cell migration.The involvement of both FAK and calpain in regulating the turnover of adhesions prompted us to investigate the cleavage of FAK by calpain as a possible mechanism by which FAK affects adhesion dynamics. We demonstrated previously that calpain-mediated proteolysis of talin regulates adhesion dynamics (17). Here, we show that FAK also regulates talin dynamics. We have identified the calpain cleavage site of FAK and have generated a mutant form of FAK that is resistant to calpain proteolysis. Expression of wild-type but not calpainresistant FAK restores the adhesion dynamics of talin in FAKdeficient cells. Taken together, our findings suggest a novel role for calpain-mediated cleavage of FAK in regulating...

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A FAK-p120RasGAP-p190RhoGAP complex regulates polarity in migrating cells

Cited by 123 publications

References 56 publications

Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Regulation of Adhesion Dynamics by Calpain-mediated Proteolysis of Focal Adhesion Kinase (FAK)

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