Article: Dumbauld DW, Lee TT, Singh A, Scrimgeour J, Gersbach CA, Zamir EA, Fu J, Chen CS, Curtis JE, Craig SW, Garcia AJ, (2013) How Vinculin Regulates Force Transmission. Proc Natl Acad Sci, 110: 9788-9793

DOI

Abstract:   Focal adhesions mediate force transfer between ECM-integrin complexes and the cytoskeleton. Although vinculin has been implicated in force transmission, few direct measurements have been made, and there is little mechanistic insight. Using vinculin-null cells expressing vinculin mutants, we demonstrate that vinculin is not required for transmission of adhesive and traction forces but is necessary for myosin contractility-dependent adhesion strength and traction force and for the coupling of cell area and traction force. Adhesion strength and traction forces depend differentially on vinculin head (V_H) and tail domains. V_H enhances adhesion strength by increasing ECM-bound integrin–talin complexes, independently from interactions with vinculin tail ligands and contractility. A full-length, autoinhibition-deficient mutant (T12) increases adhesion strength compared with V_H, implying roles for both vinculin activation and the actin-binding tail. In contrast to adhesion strength, vinculin-dependent traction forces absolutely require a full-length and activated molecule; V_H has no effect. Physical linkage of the head and tail domains is required for maximal force responses. Residence times of vinculin in focal adhesions, but not T12 or V_H, correlate with applied force, supporting a mechanosensitive model for vinculin activation in which forces stabilize vinculin’s active conformation to promote force transfer.