Potentiation of cell migration by adhesion-dependent cooperative signals from the GTPase Rac and Raf kinase

The small GTPase Rac is thought to regulate cell movement by influencing ac tin cytoskeletal organization and membrane ruffling. However, cell migratio n also depends on the activation of mitogen-activated protein kinase (MAPK) , which can regulate myosin motor function, an event critical for cell cont raction. Evidence is provided that, during active cell adhesion to the extr acellular matrix, Rac potentiates the MAPK pathway and influences cell migr ation by selectively synergizing with Raf kinase but not with Ras or MAPK k inase. In fact, the synergy between Rac and Raf kinase increases the chemot actic sensitivity of cells to epidermal growth factor by 1000-fold. Therefo re, the role of Rac in cell migration not only depends on its ability to re gulate actin cytoskeletal organization but also on its capacity to potentia te chemokine activation of MAPK in a manner that depends on active cell adh esion to the extracellular matrix.