Epidermal Growth Factor Modulates Tyrosine Phosphorylation of p130Cas

Ojaniemi, Marja; Vuori, Kristiina

doi:10.1074/jbc.272.41.25993

Cited by 103 publications

(47 citation statements)

References 58 publications

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“…We found here that the induction of Cas phosphorylation by TGF-␤ requires the presence of an intact actin cytoskeleton because the tyrosine phosphorylation can be prevented by cytochalasin D treatment. A similar situation has been observed when Cas phosphorylation was induced by EGF, IGF-1, platelet-derived growth factor, bombesin, or integrin-mediated cell adhesion (51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 76%

Involvement of Cell-Cell Interactions in the Rapid Stimulation of Cas Tyrosine Phosphorylation and Src Kinase Activity by Transforming Growth Factor-β1

Kim

Joo

2002

Journal of Biological Chemistry

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Transforming growth factor-␤ (TGF-␤) regulates a wide range of physiological and pathological cellular processes, including cell migration, mesenchymal transition, extracellular matrix synthesis, and cell death. Cas (Crk-associated substrate, 130 kDa), an adaptor protein localized at focal adhesions and stress fibers, is also known to have important functions in cell migration and the induction of immediate-early gene expression. Here, we report that a rapid and transient tyrosine phosphorylation of Cas is induced by TGF-␤1 and that E-cadherin-mediated cell-cell interaction and the Src kinase pathway are involved in this early TGF-␤ signaling. The addition of TGF-␤1 to epithelial cells rapidly induced tyrosine phosphorylation of Cas and promoted the formation of complexes between focal adhesion molecules. Cas phosphorylation required the integrity of the actin cytoskeleton but was not dependent on cell adhesion, implying that Cas-dependent signaling may be distinct from integrin signaling. TGF-␤1 also stimulated Src kinase activity, and specific inhibitors of Src completely blocked the induction of Cas phosphorylation by TGF-␤1. The Cas phosphorylation and Src kinase activation seen in our results were induced in an epithelial phenotype-specific manner. Stable transfection of E-cadherin to L929 cells and L cells as well as E-cadherin blocking assay revealed that E-cadherin-mediated cellcell interactions were essential for both Cas phosphorylation and Src kinase activation. Taken together, our data suggest that rapid Cas phosphorylation and Src kinase activation may play a novel role in TGF-␤ signal transduction. Transforming growth factor-␤ (TGF-␤)1 regulates a wide range of physiological and pathological cellular processes, including differentiation, immune response, inflammation, extracellular matrix synthesis, angiogenesis, and wound healing in humans (1-3). In epithelial and endothelial cells, TGF-␤ strongly inhibits cell growth (4, 5) and, in fibroblasts, acts in both growth stimulatory and growth inhibitory manners depending on the stage of differentiation and culture conditions (6, 7). TGF-␤ exhibits a tumor suppressor activity, and components of its signaling pathway are frequently mutated or silenced in colon and pancreatic cancers (8). However, accumulating data indicate that TGF-␤ can positively affect tumorigenesis and contribute to the progression and invasiveness of tumors (9 -11). This tumor-activating activity of TGF-␤ is associated with its ability to induce an epithelial to mesenchymal transition and stimulate cell migration (12). The epithelial to mesenchymal transition induced by TGF-␤ results in the disruption of the polarized morphology of epithelial cells, the formation of stress fibers, and an enhancement of cell migration (11, 13-15).The cell migration and reorganization of the actin cytoskeleton induced by many extracellular factors are accompanied by dramatic changes in the tyrosine phosphorylation of several signaling proteins localized at the focal adhesion plaques (16,17). The rapid...

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Section: Discussionmentioning

confidence: 76%

Involvement of Cell-Cell Interactions in the Rapid Stimulation of Cas Tyrosine Phosphorylation and Src Kinase Activity by Transforming Growth Factor-β1

Kim

Joo

2002

Journal of Biological Chemistry

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“…The mitogen-induced changes in the actin cytoskeleton are accompanied by dramatic changes in the tyrosine phosphorylation of several proteins present in focal adhesions such as vinculin, paxillin, focal adhesion kinase (FAK), p130cas, talin and tensin (Ojaniemi and Vuori, 1997). Focal adhesions are regions where indirect contact of cells with the extracellular matrix takes place.…”

Section: Introductionmentioning

confidence: 99%

RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion

Zrihan-Licht

Settleman

et al. 2000

Oncogene

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Focal adhesions and actin cytoskeleton are involved in cell growth, shape and movement and in tumor invasion. Mitogen-induced changes in actin cytoskeleton are accompanied by changes in the tyrosine phosphorylation of several focal adhesion proteins. In this study, we have investigated the role of RAFTK, a cytoplasmic tyrosine kinase related to focal adhesion kinase (FAK), in heregulin-mediated signal transduction in breast cancer cells. Stimulation of T47D cells with heregulin (HRG) induced the tyrosine phosphorylation of RAFTK and the formation of a multiprotein complex. Analyses of the members of the HRG-stimulated complex revealed that RAFTK is associated with p190 RhoGAP (p190), RasGAP and ErbB-2, and plays an essential role in mediating the tyrosine phosphorylation of p190 by Src. Mutation of the Src binding site within RAFTK (402) abolished the phosphorylation of p190. In addition, upon HRG stimulation of T47D cells, association of ErbB-2 with RAFTK was observed and found to be indirect and mediated by Src. Expression of wild-type RAFTK (WT) signi®cantly increased MDA-MB-435 and MCF-7 breast cancer cell invasion, while expression of the kinasemutated RAFTK-R457 (KM) or the Src binding site mutant RAFTK (402) did not a ect this cell invasion. Furthermore, HRG leads to the activation of MAP kinase which is mediated by RAFTK. These ®ndings indicate that RAFTK serves as a mediator and an integration point between the GAP proteins and HRG-mediated signaling in breast cancer cells, and implicate RAFTK involvement in the MAP kinase pathway and in breast cancer cell invasion.

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“…The PI 3-kinase pathway is a major pathway involved in regulating cellular actin remodeling in response to growth factor stimulation (Rijken et al, 1991;Wennstrom et al, 1994;Nobes et al, 1995;Ojaniemi and Vuori, 1997;Tsakiridis et al, 1999;Dong et al, 2000). An array of different proteins bind to the lipid products of PI 3-kinase and are recruited to the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-knockout cells

Lim

Yang²,

Zheng³

et al. 2004

Oncogene

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Mutations in the tumor suppressor protein PTEN (phosphatase and tensin homologue deleted on chromosome 10) enhance cell migration, yet the underlying molecular mechanisms remain largely uncharacterized. Loss of PTEN in mouse embryonic fibroblasts (MEFs) correlates with striking cortical actin accumulation. However, how loss of PTEN leads to cortical actin formation and whether the presence of cortical actin contributes to the increased cell migration are unclear. Here we show that overexpression of dominant-negative forms of (DN) PTEN, RhoA or its kinase-dead (KD) effector, PKN, inhibited cortical actin formation, indicating that cortical actin of Pten À/À MEFs is mediated by the PTEN/Rho/PKN pathway. However, neither DN RhoA nor KD PKN inhibited the enhanced migration of Pten À/À cells, in contrast to the inhibitory effect of DN Rac. In agreement with the previous observation that DN Akt inhibits migration of Pten À/À cells, we demonstrate here that overexpression of KD PDK-1, the Akt kinase, reduces Pten À/À cell migration. Furthermore, overexpression of DN forms of Akt, Rac, or PDK-1, all of which inhibit migration of Pten À/À cells, had no effect on cortical actin accumulation. Our findings suggest that PDK-1/Akt signaling pathway plays a major role in regulating cell migration induced by PTEN deficiency.

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Epidermal Growth Factor Modulates Tyrosine Phosphorylation of p130Cas

Cited by 103 publications

References 58 publications

Involvement of Cell-Cell Interactions in the Rapid Stimulation of Cas Tyrosine Phosphorylation and Src Kinase Activity by Transforming Growth Factor-β1

Involvement of Cell-Cell Interactions in the Rapid Stimulation of Cas Tyrosine Phosphorylation and Src Kinase Activity by Transforming Growth Factor-β1

RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion

Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-knockout cells

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