WNK1 promotes PIP? synthesis to coordinate growth factor and GPCR-Gq signaling.

ABSTRACT: PLC-? signaling is generally thought to be mediated by allosteric activation by G proteins and Ca(2+). Although availability of the phosphatidylinositol-4,5-biphosphate (PIP(2)) substrate is limiting in some cases, its production has not been shown to be independently regulated as a signaling mechanism. WNK1 protein kinase is known to regulate ion homeostasis and cause hypertension when expression is increased by gene mutations. However, its signaling functions remain largely elusive.Using diacylglycerol-stimulated TRPC6 and inositol trisphosphate-mediated Ca(2+) transients as cellular biosensors, we show that WNK1 stimulates PLC-? signaling in cells by promoting the synthesis of PIP(2) via stimulation of phosphatidylinositol 4-kinase III?. WNK1 kinase activity is not required. Stimulation of PLC-? by WNK1 and by G?(q) are synergistic; WNK1 activity is essential for regulation of PLC-? signaling by G(q)-coupled receptors, and basal input from G(q) is necessary for WNK1 signaling via PLC-?. WNK1 further amplifies PLC-? signaling when it is phosphorylated by Akt kinase in response to insulin-like growth factor.WNK1 is a novel regulator of PLC-? that acts by controlling substrate availability. WNK1 thereby coordinates signaling between G protein and Akt kinase pathways. Because PIP(2) is itself a signaling molecule, regulation of PIP(2) synthesis by WNK1 also allows the cell to initiate PLC signaling while independently controlling the effects of PIP(2) on other targets. These findings describe a new signaling pathway for Akt-activating growth factors, a mechanism for G protein-growth factor crosstalk, and a means to independently control PLC signaling and PIP(2) availability.

SUBMITTER: An SW 

PROVIDER: S-EPMC3237931 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other