PKD controls ?v?3 integrin recycling and tumor cell invasive migration through its substrate Rabaptin-5.

ABSTRACT: Integrin recycling is critical for cell migration. Protein kinase D (PKD) mediates signals from the platelet-derived growth factor receptor (PDGF-R) to control ?v?3 integrin recycling. We now show that Rabaptin-5, a Rab5 effector in endosomal membrane fusion, is a PKD substrate. PKD phosphorylates Rabaptin-5 at Ser407, and this is both necessary and sufficient for PDGF-dependent short-loop recycling of ?v?3, which in turn inhibits ?5?1 integrin recycling. Rab4, but not Rab5, interacts with phosphorylated Rabaptin-5 toward the front of migrating cells to promote delivery of ?v?3 to the leading edge, thereby driving persistent cell motility and invasion that is dependent on this integrin. Consistently, disruption of Rabaptin-5 Ser407 phosphorylation reduces persistent cell migration in 2D and ?v?3-dependent invasion. Conversely, invasive migration that is dependent on ?5?1 integrin is promoted by disrupting Rabaptin phosphorylation. These findings demonstrate that the PKD pathway couples receptor tyrosine kinase signaling to an integrin switch via Rabaptin-5 phosphorylation.

SUBMITTER: Christoforides C 

PROVIDER: S-EPMC3443396 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature