Cortactin is a filamentous actin (
F-actin)-binding protein that regulates cytoskeletal dynamics by activating the
Arp2/3 complex; it binds to
F-actin by means of six N-terminal "
cortactin repeats". Gene amplification of 11q13 and consequent overexpression of
cortactin in several human
cancers is associated with
lymph node metastasis. Overexpression as well as
tyrosine phosphorylation of
cortactin has been reported to enhance cell migration, invasion, and
metastasis. Here we report the identification of two alternative splice variants (SV1 and SV2) that affect the
cortactin repeats: SV1-cortactin lacks the 6th repeat (exon 11), whereas SV2-cortactin lacks the 5th and 6th repeats (exons 10 and 11). SV-1
cortactin is found co-expressed with wild type (wt)-
cortactin in all tissues and cell lines examined, whereas the SV2
isoform is much less abundant. SV1-cortactin binds
F-actin and promotes Arp2/3-mediated actin polymerization equally well as wt-
cortactin, whereas SV2-cortactin shows reduced
F-actin binding and polymerization. Alternative splicing of
cortactin does not affect its subcellular localization or
growth factor-induced
tyrosine phosphorylation. However, cells that overexpress SV1- or SV2-cortactin show significantly reduced cell migration when compared with wt-
cortactin-overexpressing cells. Thus, in addition to overexpression and
tyrosine phosphorylation, alternative splicing of the
F-actin binding domain of
cortactin is a new mechanism by which
cortactin influences cell migration.