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Rainero, E,Caswell, PT,Muller, PAJ,Grindlay, J,McCaffrey, MW,Zhang, QF,Wakelam, MJO,Vousden, KH,Graziani, A,Norman, JC
2012
January
The Journal of Cell Biology
Diacylglycerol kinase alpha controls RCP-dependent integrin trafficking to promote invasive migration
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Optional Fields
INDUCED CELL MOTILITY PHOSPHATIDIC-ACID ALPHA-5-BETA-1 INTEGRIN 3D MICROENVIRONMENTS ENDOCYTIC TRANSPORT RAC ACTIVATION MEMBRANE PROTEIN GENE ALPHA-V-BETA-3
196
277
295
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.
DOI 10.1083/jcb.201109112
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