Overview and Philosophy
Regulation of cell behavior by adhesion to extracellular matrix (ECM) is a fundamental fact of multicellular life. Virtually every cell in vertebrates spends at least a portion of its life cycle adhered to ECM, and this interaction critically regulates cell survival, growth, gene expression and function. Integrins are the major membrane receptors that mediate adhesion of cells to ECM. In doing so, they connect the actin cytoskeleton inside the cell to the ECM to provide mechanical integrity. My lab is among those that, in the late 1980’s, showed that integrins also transduce signals. These signals are complex and varied, and appear to mediate many if not most of the regulatory effects of ECM.
Because adhesion receptors connect ECM to intracellular filaments, they transmit forces between these structures. These may be intracellular forces from myosin that act on the surrounding ECM, or external forces acting on the cell. Integrins are involved in “measuring” the mechanical properties of the ECM, which critically govern cell behavior. Both integrins and cell-cell adhesion receptors including cadherins and the Ig family protein PECAM-1 (CD31) mediate responses of cells to applied forces such as stretch and fluid shear stress. Integrins and other cell adhesion receptors therefore stand at the intersection of a 3-way link between cell adhesion, mechanical forces and signal transduction pathways. As such understanding their behavior offers the key to understanding major biological and medical problems including anchorage dependence of growth, regulation of gene expression and differentiation by ECM, and how cells respond to mechanical stimuli (mechanotransduction).
My laboratory has therefore developed an integrated program addressing interesting problems in cell adhesion, signaling and mechanotransduction. We are currently working in 4 major areas.
|Regulation of lipid raft trafficking||Mechanotransduction by integrins|
|Fluid shear stress mechanotransduction in blood vessels||Collateral blood vessels in the mouse spinotrapezius muscle|