Concerted Activity of Tyrosine Phosphatase SHP-2 and Focal Adhesion Kinase in Regulation of Cell Motility

Mañes, Santos; Mira, Emilia; Gómez‐Moutón, Concepción; Zhao, Zijun; Lacalle, Rosa Ana; Martı́nez-A, Carlos

doi:10.1128/mcb.19.4.3125

Cited by 228 publications

(214 citation statements)

References 62 publications

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“…Moreover, our ®ndings support studies indicating that PI3-K signaling pathways, rather than MAPK activation, are critical for cell motility and cell survival (Manes et al, 1999;Tan et al, 1999), both of which may contribute to epithelial cell transformation. Cell adhesion is critical for maintaining the integrity and topography of tissues.…”

Section: Discussionsupporting

confidence: 88%

“…Others have shown that inhibition of HRG-stimulated PI3-K activation, cytoskeletal reorganization and cell migration of MCF-7 cells occurs independently of extracellular signal-regulated kinases (Adam et al, 1998). Moreover, PD-98059 has been reported to have only a marginal e ect on migration of MCF-7 breast cancer cells (Manes et al, 1999). Our data reveal that migration and spreading of glioblastoma cells were reduced by increased SIRP tyrosine phosphorylation and binding of SHP2 in cells that also displayed reduced EGFinduced PI3-K activation.…”

Section: Discussionmentioning

confidence: 99%

“…More recent reports have illustrated that SHP2 may be a general regulator of cell motility and integrin signaling (Yu et al, 1998;Oh et al, 1999) and that cooperative activity between SHP2 and Fak may be important for this regulation (Manes et al, 1999).…”

Section: Sirpa1 Regulates Glioblastoma Cell Migration and Cell Spreadmentioning

confidence: 99%

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Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

Chen

Ullrich

et al. 2000

Oncogene

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

Chen

Ullrich

et al. 2000

Oncogene

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“…Previous work has shown that SHP2 suppresses cell adhesion and enhances motility. [23][24][25][26] We sough to investigate the significance of SHP2 inhibition on breast cancer cells motility and scattering. Initially, this possibility was tested by the monolayer wound-healing assay.…”

Section: Shp2mentioning

confidence: 99%

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

Agazie

2008

Cell Death Differ

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The Src homology phosphotyrosyl phosphatase 2 (SHP2) is an essential transducer of mitogenic and cell survival signaling in the epidermal growth factor receptor (EGFR) signaling pathway. However, the role of SHP2 in aberrant EGFR and human EGFR2 (HER2) signaling and cancer, particularly in breast cancer, has not been investigated. Here, we report that SHP2 is required for mitogenic and cell survival signaling and for sustaining the transformation phenotypes of breast cancer cell lines that overexpress EGFR and HER2. Inhibition of SHP2 suppressed EGF-induced activation of the Ras-ERK and the phosphatidylinositol 3 kinase-Akt signaling pathways, abolished anchorage-independent growth, induced epithelial cell morphology and led to reversion to a normal breast epithelial phenotype. Furthermore, inhibition of SHP2 led to upregulation of E-cadherin (epithelial marker) and downregulation of fibronectin and vimentin (mesenchymal markers). These results indicate that SHP2 promotes breast cancer cell phenotypes by positively modulating mitogenic and cell survival signaling, by suppressing E-cadherin expression which is known to play a tumor suppressor role and by sustaining the mesenchymal state as evidenced by the positive impact on fibronectin and vimentin expression. Therefore, SHP2 promotes epithelial to mesenchymal transition, whereas its inhibition leads to mesenchymal to epithelial transition. On the basis of these premises, we propose that interference with SHP2 function might help treat breast cancer.

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“…Several receptor tyrosine kinases have been reported to reduce tyrosine phosphorylation of FAK, including the EGFR (37), insulin receptor (2), IGF-1R (40), and EphA2 (44). Since bile acids have no known transmembrane receptors, transactivation of receptor tyrosine kinases by DCA may be responsible for reduced tyrosine phosphorylation and catalytic activity of FAK.…”

Section: Discussionmentioning

confidence: 99%

Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2

Khare¹,

Holgren²,

Samarel³

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Khare S, Holgren C, Samarel AM. Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2. Am J Physiol Gastrointest Liver Physiol 291: G1100 -G1112, 2006. First published August 17, 2006 doi:10.1152/ajpgi.00008.2006.-Environmental factors, including dietary fats, are implicated in colonic carcinogenesis. Dietary fats modulate secondary bile acids including deoxycholic acid (DCA) concentrations in the colon, which are thought to contribute to the nutritional-related component of colon cancer risk. Here we demonstrate, for the first time, that DCA differentially regulated the sitespecific phosphorylation of focal adhesion kinase (FAK). DCA decreased adhesion of HCA-7 cells to the substratum and induced dephosphorylation of FAK at tyrosine-576/577 (Tyr-576/577) and Tyr-925. Tyrosine phosphorylation of FAK at Tyr-397 remained unaffected by DCA stimulation. Interestingly, we found that c-Src was constitutively associated with FAK and DCA actually activated Src, despite no change in FAK-397 and an inhibition of FAK-576 phosphorylation. DCA concomitantly and significantly increased association of tyrosine phosphatase ShP2 with FAK. Incubation of immunoprecipitated FAK, in vitro, with glutathione-S-transferaseShP2 fusion protein resulted in tyrosine dephosphorylation of FAK in a concentration-dependent manner. Antisense oligodeoxynucleotides directed against ShP2 decreased ShP2 protein levels and attenuated DCA-induced FAK dephosphorylation. Inhibition of FAK by adenoviral-mediated overexpression of FAK-related nonkinase and gene silencing of Shp2 both abolished DCA's effect on cell adhesion, thus providing a possible mechanism for inside-out signaling by DCA in colon cancer cells. Our results suggest that DCA differentially regulates focal adhesion complexes and that tyrosine phosphatase ShP2 has a role in DCA signaling.

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Concerted Activity of Tyrosine Phosphatase SHP-2 and Focal Adhesion Kinase in Regulation of Cell Motility

Abstract: The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF- I

Cited by 228 publications

References 62 publications

Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2

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