Cell migration: Rho GTPases lead the way

Raftopoulou, Myrto; Hall, Alan

doi:10.1016/j.ydbio.2003.06.003

Cited by 1,284 publications

(1,242 citation statements)

References 114 publications

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“…Several identified GAPs and guanine nucleotide exchange factors for Rho proteins have been implicated in cell migration and adhesion (Raftopoulou and Hall, 2004). For instance, DLC1 (deleted in liver cancer), a GAP for Rho proteins, suppresses cell proliferation, migration and invasion in hepatocellular carcinoma cells.…”

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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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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“…In contrast, active Rho is predominantly found at trailing edge of moving cells (Xu et al, 2003), its levels being inversely correlated to the levels of active Rac in many types of cells (Caron, 2003). For this reason, it is believed that, in migrating cells, active Rho forms a gradient inverse to that of Rac and Cdc42 (Raftopoulou and Hall, 2004). Ridley et al (1992) gave the first report of the crosstalk of small G-proteins: they found that Rac is needed for Rho-mediated stress fibre formation and concluded that Rac activates Rho (See also Nobes and Hall (1995)).…”

Section: Spatial Localization and Crosstalk Of Rho Gtpasesmentioning

confidence: 99%

Polarization and Movement of Keratocytes: A Multiscale Modelling Approach

et al. 2006

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“…Indeed, the inhibition of Rho, through the microinjection of the Rho inhibitor, Clostridium botulinum ADP-ribosyltransferase C3 (C3T), inhibits cell motility in many cell systems [8,9]. Initially, the role of RhoA during cell motility was thought to be restricted to the generation of contractile force and focal adhesion turnover needed for tail retraction [10,11]. This is achieved through its downstream effector, the serine/threonine kinase p160ROCK, which leads to myosin phosphorylation and actin-myosin contractility [12].…”

Section: Introductionmentioning

confidence: 99%

RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells

El‐Sibai

Pertz

Pang

et al. 2008

Experimental Cell Research

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Rho GTPases are versatile regulators of cell shape that act on the actin cytoskeleton. Studies using Rho GTPase mutants have shown that, in some cells, Rac1 and Cdc42 regulate the formation of lamellipodia and filopodia, respectively at the leading edge, whereas RhoA mediates contraction at the rear of moving cells. However, recent reports have described a zone of RhoA/ROCK activation at the front of cells undergoing motility. In this study, we use a FRET-based RhoA biosensor to show that RhoA activation localizes to the leading edge of EGF-stimulated cells. Inhibition of Rho or ROCK enhanced protrusion, yet markedly inhibited cell motility; these changes correlated with a marked activation of Rac-1 at the cell edge. Surprisingly, whereas EGF-stimulated protrusion in control MTLn3 cells is Rac-independent and Cdc42-dependent, the opposite pattern is observed in MTLn3 cells after inhibition of ROCK. Thus, Rho and ROCK suppress Rac-1 activation at the leading edge, and inhibition of ROCK causes a switch between Cdc42 and Rac-1 as the dominant Rho GTPase driving protrusion in carcinoma cells. These data describe a novel role for Rho in coordinating signaling by Rac and Cdc42.

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Cell migration: Rho GTPases lead the way

Cited by 1,284 publications

References 114 publications

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

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

Polarization and Movement of Keratocytes: A Multiscale Modelling Approach

RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells

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