PKD controls αvβ3 integrin recycling and tumor cell invasive migration through its substrate Rabaptin-5

Christoforides, C., Rainero, E., Brown, K.K., Norman, J.C. and Toker, A. (2012) PKD controls αvβ3 integrin recycling and tumor cell invasive migration through its substrate Rabaptin-5. Developmental Cell, 23(3), pp. 560-572. (doi: 10.1016/j.devcel.2012.08.008)

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 alpha v beta 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 alpha v beta 3, which in turn inhibits alpha 5 beta 1 integrin recycling. Rab4, but not Rab5, interacts with phosphorylated Rabaptin-5 toward the front of migrating cells to promote delivery of alpha v beta 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 alpha v beta 3-dependent invasion. Conversely, invasive migration that is dependent on alpha 5 beta 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Norman, Professor James and Rainero, Ms Elena
• Authors: Christoforides, C., Rainero, E., Brown, K.K., Norman, J.C., and Toker, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Developmental Cell
• ISSN: 1534-5807