RACK1 regulates VEGF/Flt1-mediated cell migration via activation of a PI3K/Akt pathway.
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Wang F, Yamauchi M, Muramatsu M, Osawa T, Tsuchida R, Shibuya M
RACK1 regulates VEGF/Flt1-mediated cell migration via activation of a PI3K/Akt pathway.
J Biol Chem. 2011 Mar 18;286(11):9097-106. doi: 10.1074/jbc.M110.165605. Epub 2011 Jan 6.
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- 21212275 [ View in PubMed]
- Abstract
Vascular endothelial growth factor (VEGF) is vital to physiological as well as pathological angiogenesis, and regulates a variety of cellular functions, largely by activating its 2 receptors, fms-like tyrosine kinase (Flt1) and kinase domain receptor (KDR). KDR plays a critical role in the proliferation of endothelial cells by controlling VEGF-induced phospholipase Cgamma-protein kinase C (PLCgamma-PKC) signaling. The function of Flt1, however, remains to be clarified. Recent evidence has indicated that Flt1 regulates the VEGF-triggered migration of endothelial cells and macrophages. Here, we show that RACK1, a ubiquitously expressed scaffolding protein, functions as an important regulator of this process. We found that RACK1 (receptor for activated protein kinase C 1) binds to Flt1 in vitro. When the endogenous expression of RACK1 was attenuated by RNA interference, the VEGF-driven migration was remarkably suppressed whereas the proliferation was unaffected in a stable Flt1-expressing cell line, AG1-G1-Flt1. Further, we demonstrated that the VEGF/Flt-mediated migration of AG1-G1-Flt1 cells occurred mainly via the activation of the PI3 kinase (PI3K)/Akt and Rac1 pathways, and that RACK1 plays a crucial regulatory role in promoting PI3K/Akt-Rac1 activation.