| First Author | Ard R | Year | 2012 |
| Journal | Mol Biol Cell | Volume | 23 |
| Issue | 20 | Pages | 4008-19 |
| PubMed ID | 22918940 | Mgi Jnum | J:199751 |
| Mgi Id | MGI:5504574 | Doi | 10.1091/mbc.E12-01-0026 |
| Citation | Ard R, et al. (2012) Diacylglycerol kinase zeta regulates RhoA activation via a kinase-independent scaffolding mechanism. Mol Biol Cell 23(20):4008-19 |
| abstractText | 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 zeta (DGKzeta), 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 Calpha (PKCalpha) selectively releases RhoA. Here we show DGKzeta is required for RhoA activation and Ser-34 phosphorylation, which were decreased in DGKzeta-deficient fibroblasts and rescued by wild-type DGKzeta or a catalytically inactive mutant. DGKzeta bound directly to the C-terminus of RhoA and the regulatory arm of RhoGDI and was required for efficient interaction of PKCalpha and RhoA. DGKzeta-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 DGKzeta-null cells. Collectively our findings suggest DGKzeta 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, DGKzeta is a critical factor linking changes in lipid signaling to actin reorganization. |
