title: PKD controls αvβ3 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 αvβ3 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 αvβ3, which in turn inhibits α5β1 integrin recycling. Rab4, but not Rab5, interacts with phosphorylated Rabaptin-5 toward the front of migrating cells to promote delivery of αvβ3 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 αvβ3-dependent invasion. Conversely, invasive migration that is dependent on α5β1 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.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Claudine
authors.initials: C
authors.lastname: Christoforides
authors.forename: Elena
authors.initials: E
authors.lastname: Rainero
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D039302:Integrin alphaVbeta3; C097227:RABEP1 protein, human; C486276:Rabep1 protein, mouse; D033921:Vesicular Transport Proteins; C089212:protein kinase D; D011493:Protein Kinase C