Protein Kinase C (PKC) δ Regulates PKCα Activity in a Syndecan-4-dependent Manner

The phosphorylation state of Ser183 in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP2), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) α. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCα activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCα and -δ were able to specifically phosphorylate Ser183in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCδ but not a DN PKCα mutant. Syndecan-4/PIP2-dependent PKCα activity was significantly increased in PKCδ DN cells, while PKCδ overexpression was accompanied by decreased PKCα activity. PKCδ-overexpressing cells exhibited a significantly lower proliferation rate and an impaired tube formation in response to FGF2, which were mirrored by similar observations in PKCα DN endothelial cells. These findings suggest that PKCδ is the kinase responsible for syndecan-4 phosphorylation, which, in turn, attenuates the cellular response to FGF2 by reducing PKCα activity. The reduced PKCα activity then leads to impaired endothelial cell function. We conclude that PKCδ regulates PKCα activity in a syndecan-4-dependent manner.