Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K

Keely, Patricia J.; Westwick, John; Whitehead, Ian P.; Der, Channing J.; Parise, Leslie V.

doi:10.1038/37656

Cited by 674 publications

(578 citation statements)

References 25 publications

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“…Thus, it is possible that not only integrin β1, but also MT1-MMP is activated by irradiation, resulting in increased migration of IR cells. Furthermore, the formation of membrane protrusions at the leading edge of migrating cells, as a result of actin reorganization, is regulated by one of the small GTPases, Rac [12], and activated Rac1 induces integrin-dependent migration in mammary epithelial cells [13]. Therefore, Rac activity might be necessary to induce invasiveness in IR cells.…”

Section: Discussionmentioning

confidence: 99%

Integrin β1-dependent invasive migration of irradiation-tolerant human lung adenocarcinoma cells in 3D collagen matrix

Ishihara

Haga

Yasuda

et al. 2010

Biochemical and Biophysical Research Communications

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Radiotherapy is one of the effective therapies used for treating various malignant tumors.However, the emergence of tolerant cells after irradiation remains problematic due to their high metastatic ability, sometimes indicative of poor prognosis. In this study, we showed that subcloned human lung adenocarcinoma cells (A549P-3) that are irradiation-tolerant indicate high invasive activity in vitro, and exhibit an integrin β1 activity-dependent migratory pattern.In collagen gel overlay assay, majority of the A549P-3 cells displayed round morphology and low migration activity, whereas a considerable number of A549P-3IR cells surviving irradiation displayed a spindle morphology and high migration rate. Blocking integrin β1 activity reduced the migration rate of A549P-3IR cells and altered the cell morphology allowing them to assume a round shape. These results suggest that the A549P-3 cells surviving irradiation acquire a highly invasive integrin β1-dependent phenotype, and integrin β1 might be a potentially effective therapeutic target in combination with radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Integrin β1-dependent invasive migration of irradiation-tolerant human lung adenocarcinoma cells in 3D collagen matrix

Ishihara

Haga

Yasuda

et al. 2010

Biochemical and Biophysical Research Communications

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“…Members of the small GTPase superfamily have emerged as key regulators of the actin cytoskeleton (Hall, 1998;; and the actin cytoskeleton has been implicated in many cellular functions, including motility, chemotaxis, cell proliferation, di erentiation, endocytosis, secretion and cell polarization (Keely et al, 1997;Nobes et al, 1995). In addition, Rho family GTPases play an important role in the activation of stress response pathways leading to the generation of pro-in¯ammatory mediators and/or apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, Rho family GTPases play an important role in the activation of stress response pathways leading to the generation of pro-in¯ammatory mediators and/or apoptotic cell death. Rho GTPases have also been implicated in the regulation of transcriptional events that contribute to cell growth regulation (Keely et al, 1997). Recently, Rac 1 and CDC42 have been implicated in the polarization of mammary epithelial cells and the promotion of their motility and invasion (Keely et al, 1997).…”

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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“…However, no direct evidence of Cdc42 to regulate the cell-cell adhesion in MDCK cells has been shown. As to the role of Cdc42 on cell migration, Cdc42 as well as Rac induces cell motility and invasion across transwells presumably through activation of phosphatidylinositol-3 kinase in mammary epithelial cells (Keely et al, 1997). On the contrary, Cdc42 is essential for cell polarity, but not for cell motility in macrophage chemotaxis (Allen et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

et al. 1999

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The Rho small G protein family consists of the Rho, Rac, and Cdc42 subfamilies and regulates various cell functions through reorganization of the actin cytoskeleton. We previously showed that the Rho subfamily regulates the formation of stress ®bers and focal adhesions whereas the Rac subfamily regulates the Ecadherin-based cell-cell adhesion in MDCK cells. We studied here the function of the Cdc42 subfamily, consisting of two members, Cdc42Hs and G25k, in cell adhesion, migration, and morphology of MDCK cells. For this purpose, we made and used MDCK cell lines stably expressing each of dominant active mutants of Cdc42Hs (sMDCK-Cdc42HsDA) and G25K (sMDCK-G25KDA). Actin ®laments at the cell-cell adhesion sites increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Both E-cadherin and b-catenin, adherens junctional proteins, at the cell-cell adhesion sites also increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Electron microscopic analysis revealed that sMDCKCdc42HsDA cells tightly contacted with each other throughout the lateral membranes. Moreover, both the HGF-and TPA-induced disruption of the cadherin-based cell-cell adhesion and the subsequent cell migration were inhibited in both sMDCK-Cdc42HsDA and -G25KDA cells. Co-expression of the dominant negative mutant of Rac1, a member of the Rac subfamily, with the dominant active mutant of Cdc42Hs did not inhibit the increased accumulation of actin ®laments at the cell-cell adhesion sites. These results suggest that the Cdc42 subfamily is involved in the cadherin-based cell-cell adhesion in a manner independent of the Rac subfamily. Furthermore, the cells were frequently enveloped by the large multinuclear cells in both sMDCK-Cdc42HsDA and -G25KDA cells. Video microscopic analysis revealed that the cells were engulfed by the large cells during cytokinesis.

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Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K

Cited by 674 publications

References 25 publications

Integrin β1-dependent invasive migration of irradiation-tolerant human lung adenocarcinoma cells in 3D collagen matrix

Integrin β1-dependent invasive migration of irradiation-tolerant human lung adenocarcinoma cells in 3D collagen matrix

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

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

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