Shc and FAK differentially regulate cell motility and directionality modulated by PTEN

Cell migration is modulated by regulatory molecules such as growth factors, oncogenes, and the tumor suppressor PTEN. We previously described inhibiti on of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK.) and p130 Crk-associated substrate (p130(Cas)). We now report a novel pathway regulating random cell motility involving Shc and mitogen-a ctivated protein (MAP) kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating directional migration. Overexpression of Shc or constitutively activated MEK1 in PTEN-reconstituted U87-MG cells stimulate d integrin-mediated MAP kinase activation and cell migration. Conversely, o verexpression of dominant negative Shc inhibited cell migration; Akt appear ed uninvolved. PTEN directly dephosphorylated Shc. The migration induced by FAK or p130(Cas) was directionally persistent and involved extensive organ ization of actin microfilaments and focal adhesions. In contrast, Shc or ME K1 induced a random type of motility associated with less actin cytoskeleta l and focal adhesion organization. These results identify two distinct, add itive pathways regulating cell migration that are downregulated by tumor su ppressor PTEN: one involves Shc, a MAP kinase pathway, and random migration , whereas the other involves FAK, p130(Cas), more extensive actin cytoskele tal organization, focal contacts, and directionally persistent cell motilit y. Integration of these pathways provides an intracellular mechanism for re gulating the speed and the directionality of cell migration.