Src, p130Cas, and Mechanotransduction in Cancer Cells

Matsui, Hiroyuki; Harada, Ichiro; Sawada, Yasuhiro

doi:10.1177/1947601912461443

Cited by 33 publications

(30 citation statements)

References 106 publications

(145 reference statements)

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“…Cas is a scaffold protein with an N-terminal SH3 domain, central region and C-terminal focal adhesion targeting (FAT) domain (Fig. 5E) (Matsui et al, 2012). The central region contains 15 repeated tyrosine sequences YxVP, followed by a PxxP binding site for the Src SH3 domain and the sequence YDYV, which when phosphorylated, binds the Src SH2 domain.…”

Section: Cul5 Regulates Cas Protein Stability and Binds Cas Through Smentioning

confidence: 99%

“…Cas is a Src substrate implicated in transformation (Matsui et al, 2012). Cas-knockout mouse fibroblasts resist transformation by active mutant Src, and Cas knockdown in breast cancer cells suppresses transformation.…”

Section: Cas Is Required For Transformation Of Cul5-deficient Cellsmentioning

confidence: 99%

“…Cas-knockout mouse fibroblasts resist transformation by active mutant Src, and Cas knockdown in breast cancer cells suppresses transformation. Cas overexpression induces membrane ruffling and stimulates invasion by Srctransformed fibroblasts and cancer cells (Bouton et al, 2001;Cabodi et al, 2006;Matsui et al, 2012;Tornillo et al, 2011;van der Flier et al, 2000). We therefore tested whether Cas is required for transformation of Cul5-deficient MCF10A cells.…”

Section: Cas Is Required For Transformation Of Cul5-deficient Cellsmentioning

confidence: 99%

“…Cas is a substrate for Src and other tyrosine kinases. Cas interacts with focal adhesion proteins and becomes tyrosine phosphorylated in response to cytoskeletal tension, and thus binds to adaptors that regulate small GTPases (Bouton et al, 2001;Matsui et al, 2012). Cas is important for the motility and proliferation of cancer cells (Cabodi et al, 2006;Tornillo et al, 2011;van der Flier et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Cullin5 destabilizes Cas to inhibit Src-dependent cell transformation

Teckchandani

Laszlo

Simó

et al. 2013

Journal of Cell Science

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Phosphorylation-dependent protein ubiquitylation and degradation provides an irreversible mechanism to terminate protein kinase signaling. Here, we report that mammary epithelial cells require cullin-5-RING-E3-ubiquitin-ligase complexes (Cul5-CRLs) to prevent transformation by a Src-Cas signaling pathway. Removal of Cul5 stimulates growth-factor-independent growth and migration, membrane dynamics and colony dysmorphogenesis, which are all dependent on the endogenous tyrosine kinase Src. Src is activated in Cul5-deficient cells, but Src activation alone is not sufficient to cause transformation. We found that Cul5 and Src together stimulate degradation of the Src substrate p130Cas (Crkassociated substrate). Phosphorylation stimulates Cas binding to the Cul5-CRL adaptor protein SOCS6 and consequent proteasomedependent degradation. Cas is necessary for the transformation of Cul5-deficient cells. Either knockdown of SOCS6 or use of a degradation-resistant Cas mutant stimulates membrane ruffling, but not other aspects of transformation. Our results show that endogenous Cul5 suppresses epithelial cell transformation by several pathways, including inhibition of Src-Cas-induced ruffling through SOCS6.

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Section: Cul5 Regulates Cas Protein Stability and Binds Cas Through Smentioning

confidence: 99%

Section: Cas Is Required For Transformation Of Cul5-deficient Cellsmentioning

confidence: 99%

Section: Cas Is Required For Transformation Of Cul5-deficient Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cullin5 destabilizes Cas to inhibit Src-dependent cell transformation

Teckchandani

Laszlo

Simó

et al. 2013

Journal of Cell Science

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“…(For a complete review of the role of Src and p130Cas in cancer cell mechanotransduction, see Ref. 91.) However, with growing evidence that integrin-based cell adhesion to the ECM plays a reduced role during tumor cell migration in confined microenvironments, the exact mechanisms by which mechanotransduction occurs may need to be redefined.…”

Section: C104 Physical Cues In Tumor Cell Migrationmentioning

confidence: 99%

Physical Biology in Cancer. 4. Physical cues guide tumor cell adhesion and migration

Stroka

Κωνσταντόπουλος

2014

American Journal of Physiology-Cell Physiology

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As tumor cells metastasize from the primary tumor location to a distant secondary site, they encounter an array of biologically and physically heterogeneous microenvironments. While it is well established that biochemical signals guide all stages of the metastatic cascade, mounting evidence indicates that physical cues also direct tumor cell behavior, including adhesion and migration phenotypes. Physical cues acting on tumor cells in vivo include extracellular matrix mechanical properties, dimensionality, and topography, as well as interstitial flow, hydrodynamic shear stresses, and local forces due to neighboring cells. State-of-the-art technologies have recently enabled us and other researchers to engineer cell microenvironments that mimic specific physical properties of the cellular milieu. Through integration of these engineering strategies, along with physics, molecular biology, and imaging techniques, we have acquired new insights into tumor cell adhesion and migration mechanisms. In this review, we focus on the extravasation and invasion stages of the metastatic cascade. We first discuss the physical role of the endothelium during tumor cell extravasation and invasion and how contractility of endothelial and tumor cells contributes to the ability of tumor cells to exit the vasculature. Next, we examine how matrix dimensionality and stiffness coregulate tumor cell adhesion and migration beyond the vasculature. Finally, we summarize how tumor cells translate and respond to physical cues through mechanotransduction. Because of the critical role of tumor cell mechanotransduction at various stages of the metastatic cascade, targeting signaling pathways involved in tumor cell mechanosensing of physical stimuli may prove to be an effective therapeutic strategy for cancer patients.

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Molecular stretching modulates mechanosensing pathways

Margadant

Yao

et al. 2017

Protein Science

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For individual cells in tissues to create the diverse forms of biological organisms, it is necessary that they must reliably sense and generate the correct forces over the correct distances and directions. There is considerable evidence that the mechanical aspects of the cellular microenvironment provide critical physical parameters to be sensed. How proteins sense forces and cellular geometry to create the correct morphology is not understood in detail but protein unfolding appears to be a major component in force and displacement sensing. Thus, the crystallographic structure of a protein domain provides only a starting point to then analyze what will be the effects of physiological forces through domain unfolding or catch-bond formation. In this review, we will discuss the recent studies of cytoskeletal and adhesion proteins that describe protein domain dynamics. Forces applied to proteins can activate or inhibit enzymes, increase or decrease protein-protein interactions, activate or inhibit protein substrates, induce catch bonds and regulate interactions with membranes or nucleic acids. Further, the dynamics of stretch-relaxation can average forces or movements to reliably regulate morphogenic movements. In the few cases where single molecule mechanics are studied under physiological conditions such as titin and talin, there are rapid cycles of stretch-relaxation that produce mechanosensing signals. Fortunately, the development of new single molecule and super-resolution imaging methods enable the analysis of single molecule mechanics in physiologically relevant conditions. Thus, we feel that stereotypical changes in cell and tissue shape involve mechanosensing that can be analyzed at the nanometer level to determine the molecular mechanisms involved.

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Src, p130Cas, and Mechanotransduction in Cancer Cells

Cited by 33 publications

References 106 publications

Cullin5 destabilizes Cas to inhibit Src-dependent cell transformation

Cullin5 destabilizes Cas to inhibit Src-dependent cell transformation

Physical Biology in Cancer. 4. Physical cues guide tumor cell adhesion and migration

Molecular stretching modulates mechanosensing pathways

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