The Regulation of Growth and Intracellular Signaling by Integrins

Meredith, Jere E.; Winitz, Sim; Lewis, Jeffrey; Hess, Sibylle; Ren, Xiang‐Dong; Renshaw, Mark W.; Schwartz, Martin A.

doi:10.1210/edrv-17-3-207

Cited by 143 publications

(68 citation statements)

References 188 publications

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“…Free GST was removed by absorption to glutathione-Sepharose. The RhoA binding domain of Rhotekin (aa 7-89) was expressed as a fusion protein with GST (GST-RBD) in E. coli and purified for use with glutathione-Sepharose as described previously (25,26). GST-RhoA was expressed in E. coli and purified with glutathione-Sepharose.…”

Section: Methodsmentioning

confidence: 99%

Identification of Potential Mechanisms for Regulation of p115 RhoGEF through Analysis of Endogenous and Mutant Forms of the Exchange Factor

Wells¹,

Gutowski²,

Bollag³

et al. 2001

Journal of Biological Chemistry

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Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli including agonists that work through G proteincoupled receptors. A direct pathway for such regulation was elucidated by the identification of p115 RhoGEF, an exchange factor for RhoA that is activated through its RGS domain by G␣ 13 . Endogenous p115 RhoGEF was found mainly in the cytosol of serum-starved cells but partially localized to membranes in cells stimulated with lysophosphatidic acid. Overexpressed p115 Rho-GEF was equally distributed between membranes and cytosol; either the RGS or pleckstrin homology domain was sufficient for this partial targeting to membranes. Removal of the pleckstrin homology domain dramatically reduced the in vitro rate of p115 RhoGEF exchange activity. Deletion of amino acids 252-288 in the linker region between the RGS domain and the Dbl homology domain or of the last 150 C-terminal amino acids resulted in non-additive reduction of in vitro exchange activity. In contrast, p115 RhoGEF pieces lacking this extended C terminus were over 5-fold more active than the full-length exchange factor in vivo. These results suggest that p115 RhoGEF is inhibited in the cellular milieu through modification or interaction of inhibitory factors with its C terminus. Endogenous p115 RhoGEF that was immunoprecipitated from cells stimulated with lysophosphatidic acid or sphingosine 1-phosphate was more active than when the enzyme was immunoprecipitated from untreated cells. This indicates an additional and potentially novel long lived mechanism for regulation of p115 RhoGEF by G protein-coupled receptors.

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Section: Methodsmentioning

confidence: 99%

Identification of Potential Mechanisms for Regulation of p115 RhoGEF through Analysis of Endogenous and Mutant Forms of the Exchange Factor

Wells¹,

Gutowski²,

Bollag³

et al. 2001

Journal of Biological Chemistry

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“…Anoikis was first documented in normal epithelial cells and endothelial cells where it helps maintain a dynamic balance between cell turnover and survival (1,2). Malignant tumor cells are often resistant to anoikis, enabling them to survive after detachment from the ECM and colonize a secondary site.…”

mentioning

confidence: 99%

Squamous Cell Carcinoma Cell Aggregates Escape Suspension-induced, p53-mediated Anoikis

Zhang

Lü

Dazin

et al. 2004

Journal of Biological Chemistry

116

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Disrupting cell adhesion to the extracellular matrix (ECM) 1 rapidly induces programmed cell death, a response that has been termed anoikis (1). Anoikis was first documented in normal epithelial cells and endothelial cells where it helps maintain a dynamic balance between cell turnover and survival (1, 2). Malignant tumor cells are often resistant to anoikis, enabling them to survive after detachment from the ECM and colonize a secondary site. Resistance to anoikis has been described in many types of human malignancies, including gastric cancer, mammary tumors, colon cancers, osteosarcomas, and lung carcinomas (3-7), but little is known about it in the progression of human oral squamous cell (SCC) carcinoma. Oral cancer is the sixth most common solid tumor, accounting for 5.5% of all malignancies worldwide (8). SCC accounts for 96% of all tumors of the oral cavity (9), and many patients with these tumors die from metastatic disease (10).What factors promote anchorage-independent survival and spread of tumor cells? One possibility is survival signals mediated through cell-cell contacts. One factor that promotes the survival of ECM-deprived SCC cells by such contact is the cadherin receptor family (11). A second possibility is the integrin receptor family, because integrins play a role in multiple steps in tumorigenesis, including cell spreading, invasion, and survival. Integrins are heterodimeric, cation-dependent cell membrane adhesion molecules that mediate cell-cell and cell-ECM interactions (12). In mammals, at least 16 ␣ and 8 ␤ subunits have been reported that combine into 22 different heterodimers, each with specific recognition and affinities for various ECM components or other cell-bearing adhesion molecules (13,14). Integrin expression patterns are often altered during tumor development. Metastasis requires changes in integrin expression. In SCC cells, substantial evidence demonstrates altered integrin expression in tumorigenesis compared with the native state. Alterations in the expression and function of integrins are also associated with anoikis (15, 16).One likely mechanism for integrin-mediated survival and resistance to anoikis is signal transduction through activation of intracellular tyrosine kinases, such as focal adhesion kinase (FAK). FAK is a non-receptor protein-tyrosine kinase that indirectly localizes to sites of integrin clustering through C-terminal domain-mediated interaction with integrin-associated proteins such as paxillin and talin (17). In vitro, its N-terminal domain binds to sequences in the cytoplasmic domain of ␤ integrin subunits (18). Elevation of the phosphotyrosine content of FAK correlates directly with increased cell adhesion. Focal adhesion complexes formed in mouse fibroblasts plated on fibronectin have 2.5-fold higher FAK phosphorylation activity than cells plated on polylysine, where adherence is integrinindependent and the phosphotyrosine content of FAK is minimal (19). Tyrosine 397 is the major site for phosphorylation and catalytic activity of FAK both in vivo and...

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“…Correspondingly, binding of some carcinomas to the ECM protects against apoptosis initiated by DNA damage (22). However, in transformed epithelial cells and fibroblastic cell types, ligation of integrins is not required for survival, and detachment from the ECM is not sufficient to trigger apoptosis (23).…”

mentioning

confidence: 99%

Integrins regulate the apoptotic response to DNA damage through modulation of p53

Lewis

Truong

Schwartz

2002

Proc. Natl. Acad. Sci. U.S.A.

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The Regulation of Growth and Intracellular Signaling by Integrins

Cited by 143 publications

References 188 publications

Identification of Potential Mechanisms for Regulation of p115 RhoGEF through Analysis of Endogenous and Mutant Forms of the Exchange Factor

Identification of Potential Mechanisms for Regulation of p115 RhoGEF through Analysis of Endogenous and Mutant Forms of the Exchange Factor

Squamous Cell Carcinoma Cell Aggregates Escape Suspension-induced, p53-mediated Anoikis

Integrins regulate the apoptotic response to DNA damage through modulation of p53

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