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Diacylglycerol kinase ? regulates RhoA activation via a kinase-independent scaffolding mechanism.


ABSTRACT: Rho GTPases share a common inhibitor, Rho guanine nucleotide dissociation inhibitor (RhoGDI), which regulates their expression levels, membrane localization, and activation state. The selective dissociation of individual Rho GTPases from RhoGDI ensures appropriate responses to cellular signals, but the underlying mechanisms are unclear. Diacylglycerol kinase ? (DGK?), which phosphorylates diacylglycerol to yield phosphatidic acid, selectively dissociates Rac1 by stimulating PAK1-mediated phosphorylation of RhoGDI on Ser-101/174. Similarly, phosphorylation of RhoGDI on Ser-34 by protein kinase C? (PKC?) selectively releases RhoA. Here we show DGK? is required for RhoA activation and Ser-34 phosphorylation, which were decreased in DGK?-deficient fibroblasts and rescued by wild-type DGK? or a catalytically inactive mutant. DGK? bound directly to the C-terminus of RhoA and the regulatory arm of RhoGDI and was required for efficient interaction of PKC? and RhoA. DGK?-null fibroblasts had condensed F-actin bundles and altered focal adhesion distribution, indicative of aberrant RhoA signaling. Two targets of the RhoA effector ROCK showed reduced phosphorylation in DGK?-null cells. Collectively our findings suggest DGK? functions as a scaffold to assemble a signaling complex that functions as a RhoA-selective, GDI dissociation factor. As a regulator of Rac1 and RhoA activity, DGK? is a critical factor linking changes in lipid signaling to actin reorganization.

SUBMITTER: Ard R 

PROVIDER: S-EPMC3469516 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Diacylglycerol kinase ζ regulates RhoA activation via a kinase-independent scaffolding mechanism.

Ard Ryan R   Mulatz Kirk K   Abramovici Hanan H   Maillet Jean-Christian JC   Fottinger Alexandra A   Foley Tanya T   Byham Michèle-Renée MR   Iqbal Tasfia Ahmed TA   Yoneda Atsuko A   Couchman John R JR   Parks Robin J RJ   Gee Stephen H SH  

Molecular biology of the cell 20120823 20


Rho GTPases share a common inhibitor, Rho guanine nucleotide dissociation inhibitor (RhoGDI), which regulates their expression levels, membrane localization, and activation state. The selective dissociation of individual Rho GTPases from RhoGDI ensures appropriate responses to cellular signals, but the underlying mechanisms are unclear. Diacylglycerol kinase ζ (DGKζ), which phosphorylates diacylglycerol to yield phosphatidic acid, selectively dissociates Rac1 by stimulating PAK1-mediated phospho  ...[more]

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