Adaptor Protein Crk Induces Src-Dependent Activation of p38 MAPK in Regulation of Synovial Sarcoma Cell Proliferation

Watanabe, Takuya; Tsuda, Masumi; Tanaka, Shinya; Ohba, Yusuke; Kawaguchi, Hideaki; Majima, Tokifumi; Sawa, Hirofumi; Minami, Akio

doi:10.1158/1541-7786.mcr-09-0064

Cited by 42 publications

(44 citation statements)

References 47 publications

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“…In summary, our data in detail substantiate previous findings on the relevance of SRC in synovial sarcomas (40). For the first time, it is systematically shown that the SRC signaling network is commonly activated in synovial sarcomas and that targeting SRC results in substantial effects on tumor cell growth and motility.…”

Section: Discussionsupporting

confidence: 90%

SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells

et al. 2013

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Synovial sarcoma is a soft-tissue malignancy characterized by a reciprocal t(X;18) translocation encoding a chimeric transcriptional modifier. Several receptor tyrosine kinases have been found activated in synovial sarcoma; however, no convincing therapeutic concept has emerged from these findings. On the basis of the results of phosphokinase screening arrays, we here investigate the functional and therapeutic relevance of the SRC kinase in synovial sarcoma. Immunohistochemistry of phosphorylated SRC and its regulators CSK and PTP1B (PTPN1) was conducted in 30 synovial sarcomas. Functional aspects of SRC, including dependence of SRC activation on the SS18/SSX fusion proteins, were analyzed in vitro. Eventually, synovial sarcoma xenografts were treated with the SRC inhibitor dasatinib in vivo. Activated phospho (p)-(Tyr416)-SRC was detected in the majority of tumors; dysregulation of CSK or PTP1B was excluded as the reason for the activation of the kinase. Expression of the SS18/SSX fusion proteins in T-REx-293 cells was associated with increased p-(Tyr416)-SRC levels, linked with an induction of the insulin-like growth factor pathway.

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Section: Discussionsupporting

confidence: 90%

SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells

et al. 2013

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“…Y221 in the C-SH3 of CrkII is a defined regulatory site [38], whereas CrkI does not contain this tyrosine residue, but holds much stronger transformative activity as compared with CrkII [30,31]. In contrast to previous studies that suggest that CrkI may function in a constitutively active form [39], our findings indicate that the phosphorylation status of CrkI can be altered by phosphatases like PTPN4 and some other unknown kinase(s). However, two questions remain unanswered.…”

Section: Discussioncontrasting

confidence: 79%

PTPN4 negatively regulates CrkI in human cell lines

Zhou

Wan

Shan

et al. 2013

Cellular and Molecular Biology Letters

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PTPN4 is a widely expressed non-receptor protein tyrosine phosphatase. Although its overexpression inhibits cell growth, the proteins with which it interacts to regulate cell growth are unknown. In this study, we identified CrkI as a PTPN4-interacting protein using a yeast two-hybrid, and confirmed this interaction using in vitro GST pull-down and coimmunoprecipitation and co-localization assays. We further determined the interactional regions as the SH3 domain of CrkI and the proline-rich region between amino acids 462 and 468 of PTPN4. Notably, overexpression of PTPN4 inhibits CrkI-mediated proliferation and wound healing of HEK293T cells, while knockdown of PTPN4 by siRNA in Hep3B cells enhances CrkI-mediated cell growth and motility. Moreover, our data show that ectopic expression of PTPN4 reduces the phosphorylation level of CrkI in HEK293T cells. These findings suggest that PTPN4 negatively regulates cell proliferation and motility through dephosphorylation of CrkI.

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“…3) (Friedland et al, 2009;Schroer, 2014). Non-canonical TGF-β1 signaling through Src and p38 promotes the production of α-SMA in AVICs by the transcription factors myocardin related transcription factor (MRTF) and serum response factor (SRF) (Elberg et al, 2008;Hutcheson et al, 2012;Watanabe et al, 2009). FGF-2 signaling through FAK and ERK1/2 has been shown to prevent MyoFB differentiation in MEFs and to reverse TGF-β1-mediated expression of α-SMA (Greenberg et al, 2006;Kawai-Kowase et al, 2004;Schroer, 2014).…”

Section: Mechanosensors Of Stressmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

117

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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Adaptor Protein Crk Induces Src-Dependent Activation of p38 MAPK in Regulation of Synovial Sarcoma Cell Proliferation

Cited by 42 publications

References 47 publications

SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells

SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells

PTPN4 negatively regulates CrkI in human cell lines

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

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