期刊
DEVELOPMENTAL CELL
卷 23, 期 3, 页码 560-572出版社
CELL PRESS
DOI: 10.1016/j.devcel.2012.08.008
关键词
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资金
- National Institutes of Health [CA075134, CA096710]
- Department of Defense Breast Cancer Research program [BC061404]
- Cancer Research UK
- Genesis Oncology Trust of New Zealand [GOT-1040-JGPDF]
- West of Scotland Women's Bowling Association
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.
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