Extracellular Signal-Regulated Kinase 1 Interacts with and Phosphorylates CdGAP at an Important Regulatory Site

Tcherkezian, Joseph; Danek, Eric I.; Jenna, Sarah; Triki, Ibtissem; Lamarche-Vane, Nathalie

doi:10.1128/mcb.25.15.6314-6329.2005

Cited by 41 publications

(67 citation statements)

References 38 publications

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“…In fact, CdGAP-PRD was sufficient to rescue the ability of TGFb to induce cell migration and invasion in Neu-NTexpressing cells. This domain of CdGAP interacts with the protein kinases ERK1/2, p90RSK-1, GSK3 and has been shown to be highly phosphorylated on serine and threonine residues (Tcherkezian et al, 2005;Danek et al, 2007). Thr-776, a common phosphorylation site for both ERK1/2 and GSK-3, is an important negative regulatory site of CdGAP activity (Tcherkezian et al, 2005;Danek et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…This domain of CdGAP interacts with the protein kinases ERK1/2, p90RSK-1, GSK3 and has been shown to be highly phosphorylated on serine and threonine residues (Tcherkezian et al, 2005;Danek et al, 2007). Thr-776, a common phosphorylation site for both ERK1/2 and GSK-3, is an important negative regulatory site of CdGAP activity (Tcherkezian et al, 2005;Danek et al, 2007). The mutant protein CdGAP-T776A, showing higher GAP activity towards Rac1 (Tcherkezian et al, 2005), was still able to rescue TGFbmediated cell migration, suggesting that this ERK/ GSK-3 phosphorylation site does not contribute to CdGAP function in TGFb-induced cell migration.…”

Section: Discussionmentioning

confidence: 99%

“…More importantly, CdGAP-PRD was sufficient to rescue TGFb-induced cell migration and invasion (Figures 7e and f). We have previously shown that CdGAP-PRD is highly phosphorylated on serine and threonine residues, and in particular, threonine-776 is an in vivo regulatory target site of ERK1/2 and GSK3 (Tcherkezian et al, 2005;Danek et al, 2007). However, expression of the mutant protein mCdGAP-T776A was still able to rescue TGFb-induced cell migration, suggesting that this ERK/ GSK-3 phosphorylation site does not participate to those CdGAP functions that promote TGFb-induced cell migration (Figure 7e).…”

Section: Depletion Of Cdgap Induces E-cadherin Protein Expression In mentioning

confidence: 93%

“…Mouse and hCdGAP constructs were as described previously (Southgate et al, submitted;Tcherkezian et al, 2005Tcherkezian et al, , 2006.…”

Section: Methodsmentioning

confidence: 99%

“…CdGAP contains a N-terminal GAP domain, a basic central region and a proline-rich domain (PRD) with an extended C-terminal domain (Lamarche-Vane and Hall, 1998;Jenna et al, 2002;Tcherkezian et al, 2006). We have previously shown that CdGAP is a substrate of ERK/GSK-3 and mediates cross talk between the Ras/MAP kinase pathway and regulation of Rac1 activity (Tcherkezian et al, 2005;Danek et al, 2007). Furthermore, CdGAP is a serum-inducible gene (Danek et al, 2007) and is required for normal cell spreading, polarized lamellipodia and cell migration; important cellular processes involved in cancer progression (Lalonde et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Depletion Of Cdgap Induces E-cadherin Protein Expression In mentioning

confidence: 93%

“…Mouse and hCdGAP constructs were as described previously (Southgate et al, submitted;Tcherkezian et al, 2005Tcherkezian et al, , 2006.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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CdGAP regulates cell migration and adhesion dynamics in two‐and three‐dimensional matrix environments

2012

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CdGAP is a Rac1/Cdc42 specific GTPase activating protein that localizes to cell–matrix adhesions through an interaction with the adhesion scaffold α-parvin/actopaxin to regulate lamellipodia formation and cell spreading. Herein we demonstrate, using a combination of siRNA-mediated silencing and over expression, that cdGAP negatively regulates directed and random migration by controlling adhesion maturation and dynamics through the regulation of both adhesion assembly and disassembly. Interestingly, cdGAP was also localized to adhesions formed in three-dimensional matrix environments and cdGAP depletion promoted cancer cell migration and invasion through 3D matrices. These findings highlight the importance of GAP proteins in the regulation of Rho family GTPases and the co-ordination of the cell migration machinery.

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MAPK3 deficiency drives autoimmunity via DC arming

et al. 2010

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DC are professional APC that instruct T cells during the inflammatory course of EAE. We have previously shown that MAPK3 (Erk1) is important for the induction of T-cell anergy. Our goal was to determine the influence of MAPK3 on the capacity of DC to arm T-cell responses in autoimmunity. We report that DC from Mapk3 À/À mice have a significantly higher membrane expression of CD86 and MHC-II and -when loaded with the myelin oligodendrocyte glycoprotein -show a superior capacity to prime naïve T cells towards an inflammatory phenotype than Mapk3 1/1 DC. Nonetheless and as previously described, Mapk3 À/À mice were only slightly but not significantly more susceptible to myelin oligodendrocyte glycoprotein-induced EAE than WT littermate mice. However, Mapk3 1/1 mice engrafted with Mapk3 À/À BM (KO-WT) developed a severe form of EAE, in direct contrast to WT-KO mice, which were even less sick than control WT-WT mice. An infiltration of DC and accumulation of Th17 cells was also observed in the CNS of KO-WT mice. Therefore, triggering of MAPK3 in the periphery might be a therapeutic option for the treatment of neuroinflammation since absence of this kinase in the immune system leads to severe EAE.Key words: DC . EAE . MAPK3 . T-cell priming IntroductionIn order for living organisms to build up an immune response against dangerous entities it is fundamental that DC continuously patrol the periphery and sample their environment for danger signals [1]. Their distinct capacity to mobilize swiftly to lymphoid organs and alternate between antigen uptake and presentation makes DC decision-makers for inducing antigen-specific T-cell responses [2]. Previously we showed that the activation of MAPK3 or Erk1 but not its isoform MAPK1 (Erk2) accompanies, and is necessary for, the induction of T-cell anergy [3]. Since their identification [4], MAPK3 and its isoforms have been commonly ascribed analogous downstream functions due to their Ã These authors contributed equally to this work. 1486striking similarities. However, it is becoming increasingly clear that these isoforms -particularly MAPK3 and MAPK1 -have explicitly different functions. While MAPK1 has a more pronounced role in cell proliferation and developmental processes [5][6][7], MAPK3 does not seem to be required during development and its deficiency may be compensated for by MAPK1. In fact while Mapk À/À mice are lethal, Mapk3 À/À mice are viable and develop normally [8]. However, when challenged with CNS antigen Mapk3 À/À mice are more susceptible to undergo EAE [9,10]. So far, a deficiency of MAPK3 in the CNS has been associated with facilitated learning and long-term memory [11]. In the immune system, MAPK3 has been reported to play a key role in positive selection during T-cell development [8,12] and we have previously shown MAPK3 activation to be necessary for the induction of T-cell anergy [3].In this study we report that MAPK3 acts as a negative regulator of DC that controls their strength to prime T cells towards an inflammatory phenotype. Mapk3 À/À DC expressed ...

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Extracellular Signal-Regulated Kinase 1 Interacts with and Phosphorylates CdGAP at an Important Regulatory Site

Cited by 41 publications

References 38 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

CdGAP regulates cell migration and adhesion dynamics in two‐and three‐dimensional matrix environments

MAPK3 deficiency drives autoimmunity via DC arming

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