Stochastic dynamics of membrane protrusion mediated by the DOCK180/Rac pathway in migrating cells

Cell migration is regulated by processes that control adhesion to extracellular matrix (ECM) and force generation. While our fundamental understanding of how these control mechanisms are actuated at the molecular level (signal transduction) has been refined over many years, appreciation of their dynamics has grown more recently. Here, we formulate and analyze by stochastic simulation a quantitative model of signaling mediated by the integrin family of adhesion receptors. Nascent adhesions foster the activation of the small GTPase Rac by at least two distinct signaling pathways, one of which involves tyrosine phosphorylation of the scaffold protein paxillin and formation of multiprotein complexes containing the guanine nucleotide exchange factor DOCK180. Active Rac promotes protrusion of the cell's leading edge, which in turn enhances the rate of nascent adhesion nucleation; we call this feedback mechanism the core protrusion cycle. Protrusion is antagonized by stable adhesions, which form by myosin-dependent maturation of nascent adhesions, and we propose here a feedforward mechanism mediated by the tyrosine kinase c-Src by which this antagonism is regulated so as to allow transient protrusion at higher densities of ECM. We show that this "buffering of inhibition" mechanism, coupled with the core protrusion cycle, is capable of tuning the frequencies of protrusion and adhesion maturation events.