SRC-3Δ4 Mediates the Interaction of EGFR with FAK to Promote Cell Migration

EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3 Delta 4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src. We identify three PAK1-mediated phosphorylations in SRC-3 Delta 4 that promote the localization of SRC-3 Delta 4 to the plasma membrane and mediate the interactions with EGFR and FAK Importantly, overexpression of SRC-3 Delta 4 promotes MDA-MB231-induced breast tumor metastasis. Our findings identify phosphorylated SRC-3 Delta 4 as a missing adaptor between EGFR and its downstream signaling molecule FAK to coordinately regulate EGF-induced cell migration. Our study also reveals that a nuclear receptor coactivator can act in the periphery of a cell to directly mediate activation of an enzyme.