Cellular mechanotransduction - the mechanism by which cells sense mechanical forces and convert them into changes in cellular biochemistry - is critical for control of development of both large and small blood vessels. Deregulation of this process may contribute to the development of various angiogenesis-dependent diseases. Force transduction from the extracellular matrix (ECM) to the cell occurs mainly through transmembrane receptors called integrins. Many signaling cascades are activated by integrins in a force- dependent manner but the initial mechanism of mechanochemical signal conversion is unclear. Recent data from Dr. Ingber's laboratory shows that large, heterotrimeric G proteins are involved in integrin-dependent responses to force and may bind directly to the integrin. Based on these data I propose to determine the molecular mechanism of G protein recruitment to and activation by integrins. I will probe integrin mutants using magnetic micromanipulation, biochemistry and confocal microscopy to determine which domains of integrin are required for integrin-dependent response to force. These studies will improve our understanding of mechanotransduction and could suggest novel anti-angiogenic drug targets.
| Matthews, Benjamin D; Thodeti, Charles K; Tytell, Jessica D et al. (2010) Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. Integr Biol (Camb) 2:435-42 |
| Alenghat, Francis J; Tytell, Jessica D; Thodeti, Charles K et al. (2009) Mechanical control of cAMP signaling through integrins is mediated by the heterotrimeric Galphas protein. J Cell Biochem 106:529-38 |
