Interleukin-1 Receptor-Associated Kinase-1 (IRAK-1) functionally associates with PKCɛ and VASP in the regulation of macrophage migration

Abstract

Macrophage migration is mediated by complex cellular signaling processes and cytoskeleton re-arrangement. In particular, recent advances indicate that the innate immunity signaling process plays a key role in the regulation of macrophage migration. In this report, we have provided evidence demonstrating the involvement of a key innate immunity signaling kinase, Interleukin-1 Receptor-Associated Kinase-1 (IRAK-1) as a critical modulator of macrophage migration. Macrophage migration induced by phorbol 12-myristate 13-acetate (PMA) is significantly attenuated in IRAK-1−/− macrophages as compared to wild type macrophages. Mechanistically, we demonstrated that IRAK-1 works downstream of PKCɛ and upstream of VASP, a member of Ena/VASP family proteins. IRAK-1 forms a close complex with PKCɛ as well as VASP, and participates in PMA-induced phosphorylation of VASP. Notably, IRAK-1 contains a novel EVH1 domain binding motif (L167WPPPP) within its N-terminus, which is responsible for its interaction with VASP. The mutant IRAK-1 (L167A/W168A) fails to associate with VASP. Our findings provide a novel facet regarding the molecular signaling process regulating macrophage migration.