Crk family adaptors–signalling complex formation and biological roles

Feller, Stephan M.

doi:10.1038/sj.onc.1204779

Cited by 439 publications

(527 citation statements)

References 368 publications

(306 reference statements)

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“…Crk transmits signals from tyrosine-phosphorylated proteins including the components of focal adhesion, growth factor receptors, and signalling scaffold proteins, by binding to them via SH2 domain [1]. Crk associates with GEFs (guanine-nucleotides exchange factors) such as C3G and Dock180 those activate Rap1/R-Ras and Rac, respectively, and controls cell adhesion, proliferation, and motility [3,4].…”

Section: Introductionmentioning

confidence: 99%

Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4

Wang

Tabu

Kimura

et al. 2007

Biochemical and Biophysical Research Communications

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Section: Introductionmentioning

confidence: 99%

Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4

Wang

Tabu

Kimura

et al. 2007

Biochemical and Biophysical Research Communications

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“…Since the isolation of mammalian homologues of viral Crk, such as c-Crk-I and c-Crk-II (Matsuda et al, 1992b), Crk has been shown to transmit signals under various stimuli including epidermal growth factor, neurotrophic growth factor and fibroblast growth factor (Tanaka et al, 1993;Feller, 2001). c-Crk-II possesses one SH2 domain at the N-terminus and two SH3 domains, wheras its alternative splicing product c-Crk-I is composed of the SH2 domain and a single SH3 domain.…”

Section: Introductionmentioning

confidence: 99%

“…c-Crk-II possesses one SH2 domain at the N-terminus and two SH3 domains, wheras its alternative splicing product c-Crk-I is composed of the SH2 domain and a single SH3 domain. The SH2 domain is responsible for binding to the tyrosine phosphorylated form of 130 Cas and paxillin, suggesting a role for Crk in regulation of the cytoskeleton (Feller, 2001). In fact, Crk has been shown to transmit signals to small GTPases by association with its downstream effectors such as Dock180 and C3G, which are the guanine-nucleotide exchange factors (GEFs) for Rac and Rap, respectively (Tanaka et al, 1994;Gotoh et al, 1995;Hasegawa et al, 1996;Kiyokawa et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS

et al. 2006

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Signaling adaptor protein Crk regulates cell motility and growth through its targets Dock180 and C3G, those are the guanine-nucleotide exchange factors (GEFs) for small GTPases Rac and Rap, respectively. Recently, overexpression of Crk has been reported in various human cancers. To define the role for Crk in human cancer cells, Crk expression was targeted in the human ovarian cancer cell line MCAS through RNA interference, resulting in the establishment of three Crk knockdown cell lines. These cell lines exhibited disorganized actin fibers, reduced number of focal adhesions, and abolishment of lamellipodia formation. Decreased Rac activity was demonstrated by pull-down assay and FRET-based timelapse microscopy, in association with suppression of both motility and invasion by phagokinetic track assay and transwell assay in these cells. Furthermore, Crk knockdown cells exhibited slow growth rates in culture and suppressed anchorage-dependent growth in soft agar. Tumor forming potential in nude mice was attenuated, and intraperitoneal dissemination was not observed when Crk knockdown cells were injected into the peritoneal cavity. These results suggest that the Crk is a key component of focal adhesion and involved in cell growth, invasion, and dissemination of human ovarian cancer cell line MCAS.

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“…It was reported that these two phosphorylation sites of paxillin serve as docking sites for the downstream effector Crk (Turner, 2000). Crk, known as an adaptor protein containing both SH2 and SH3 domains, mediates various signaling pathways through its SH3 binding partners, such as C3G and DOCK180 (Feller, 2001). To determine how TIMP-2 signaling affects the molecular interaction of paxillin, we immunoprecipitated TIMP-2-treated cell lysates with antipaxillin antibody and analysed by immunoblotting.…”

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confidence: 99%

TIMP-2 upregulates RECK expression via dephosphorylation of paxillin tyrosine residues 31 and 118

Diaz

Wei

et al. 2006

Oncogene

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We previously demonstrated that TIMP-2 increases the association of Crk with C3G and via subsequent activation of Rap1 enhances the expression of RECK, a membrane-anchored MMP inhibitor. In the present study, we investigate the mechanism of how the TIMP-2 signal is transduced from the a3b1 integrin receptor to the Crk-C3G-Rap1 molecular complex. TIMP-2 treatment of human microvascular endothelial cells (hMVECs) increased the phosphorylation levels of Src at Tyr-527, the negative regulatory site, through enhanced association of Src with Csk. This results in the reduction of Src kinase activity and dephosphorylation of paxillin at Tyr-31/118, the target sites for Src kinase phosphorylation and also the binding sites for the downstream effector Crk. Such TIMP-2 effects accompany the disassembly of paxillinCrk-DOCK180 molecular complex and, in turn, Rac1 inactivation. On the contrary, levels of paxillin-Crk-C3G complex formation are not reduced, rather slightly increased, which is consistent with our previous finding. Therefore, TIMP-2-mediated inhibition of Src kinase activity leads to the signaling switch from Rac1 to Rap1, thereby leading to enhanced RECK expression.

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Crk family adaptors–signalling complex formation and biological roles

Cited by 439 publications

References 368 publications

Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4

Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4

Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS

TIMP-2 upregulates RECK expression via dephosphorylation of paxillin tyrosine residues 31 and 118

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