Force sensing by mechanical extension of the Src family kinase substrate p130Cas.

By Y. Sawada, M. Tamada, Benjamin J. Dubin-Thaler, Oksana Cherniavskaya, R. Sakai, Sakae Tanaka, M. Sheetz. Cell, 2006

956 citations recorded by the source corpus.

How physical force is sensed by cells and transduced into cellular signaling pathways is poorly understood. Previously, we showed that tyrosine phosphorylation of p130Cas (Cas) in a cytoskeletal complex is involved in force-dependent activation of the small GTPase Rap1. Here, we mechanically extended bacterially expressed Cas substrate domain protein (CasSD) in vitro and found a remarkable enhancement of phosphorylation by Src family kinases with no apparent change in kinase activity. Using an antibody that recognized extended CasSD in vitro, we observed Cas extension in intact cells in the peripheral regions of spreading cells, where higher traction forces are expected and where phosphorylated Cas was detected, suggesting that the in vitro extension and phosphorylation of CasSD are relevant to physiological force transduction. Thus, we propose that Cas acts as a primary force sensor, transducing force into mechanical extension and thereby priming phosphorylation and activation of downstream signaling.

Subfields: Atomic and Molecular Physics, and Optics, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7fff652a3a10fd71543992f9003eaad301b76dd2

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Citations in the corpus

Non-muscle myosin II takes centre stage in cell adhesion and migration (2009, neutral): “The second hypothesis is that NM II-generated force induces conformational changes that expose cryptic binding or activation sites in key adhesion component”
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin signaling (2009, background): “Force increases integrin expression, activity, and focal adhesions (Paszek et al., 2005; Sawada et al., 2006).”
Cell adhesion: integrating cytoskeletal dynamics and cellular tension (2010, background): “Other adhesion-associated molecules, such as paxillin and CRK-associated SRC substrate ( CAS ; also known as p130cas), may also change conformation under tension (or tension-induced signals) to reveal new protein-binding and/or phosphorylation site”
The myofibroblast: paradigm for a mechanically active cell. (2010, background): “, 2005), and p130CAS (Sawada et al., 2006).”
Myosin II dynamics are regulated by tension in intercalating cells (2009, background): “Finally, mechanical tension can alter signaling pathways directly through force-dependent changes in protein interactions (Sawada et al., 2006; del Rio et al., 2009).”
α-Catenin as a tension transducer that induces adherens junction development (2010, background): “Several proteins have recently been shown to change their conformation according to applied force”
Extracellular matrix: a dynamic niche component during cancer progression (2012, neutral): “Many of the focal adhesion components, including talin and p130Cas, undergo conforma tional changes that impart functional consequences in response to applied force (Sawada et al., 2006; del Rio et al., 2009; Wang et al., 2011).”
Mechanical control of stem cell differentiation (2008, background): “, 2006), mechanosensitive ion channels (Sukharev and Corey, 2004),conformational change of cytoskeletal proteins (Sawada et al., 2006; Johnson et al., 2007), the nuclear lamina or nuclear deformations (Lammerding et al.”
Mechanical Integration of Actin and Adhesion Dynamics in Cell Migration (2010, background): “In addition, in vitro experimental evidence suggests that forced unfolding of talin promotes vinculin binding (del Rio et al. 2009), whereas stretching p130cas unmasks a tyrosine substrate for Src family kinases (Sawada et al. 2006).”