Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration

Inhibition of alpha v beta 3 integrin or expression of oncogenic mutants of p53 promote invasive cell migration by enhancing endosomal recycling of alpha 5 beta 1 integrin under control of the Rab11 effector Rab-coupling protein (RCP). In this paper, we show that diacylglycerol kinase alpha (DGK-alpha), which phosphorylates diacylglycerol to phosphatidic acid (PA), was required for RCP to be mobilized to and tethered at the tips of invasive pseudopods and to allow RCP-dependent alpha 5 beta 1 recycling and the resulting invasiveness of tumor cells. Expression of a constitutive-active mutant of DGK-alpha drove RCP-dependent invasion in the absence of mutant p53 expression or alpha v beta 3 inhibition, and conversely, an RCP mutant lacking the PA-binding C2 domain was not capable of being tethered at pseudopod tips. These data demonstrate that generation of PA downstream of DGK-alpha is essential to connect expression of mutant p53s or inhibition of alpha v beta 3 to RCP and for this Rab11 effector to drive the trafficking of alpha 5 beta 1 that is required for tumor cell invasion through three-dimensional matrices.