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

SummaryEGF 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-3Δ4, 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-3Δ4 that promote the localization of SRC-3Δ4 to the plasma membrane and mediate the interactions with EGFR and FAK. Importantly, overexpression of SRC-3Δ4 promotes MDA-MB231-induced breast tumor metastasis. Our findings identify phosphorylated SRC-3Δ4 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.

► SRC-3Δ4 is an SRC-3 isoform that localizes in the cytoplasm with FAK
► SRC-3Δ4 bridges EGFR to FAK to mediate EGF-induced cell migration
► SRC-3Δ4 phosphorylations by PAK-1 mediate binding of SRC-3Δ4 to EGFR and FAK
► Coactivators can “directly” activate cytoplasmic enzymes