WNK1 promotes PIP2 synthesis to coordinate growth factor and GPCR-Gq signaling

Sung Wan An, Seung Kuy Cha, Joonho Yoon, Seungwoo Chang, Elliott M. Ross, Chou Long Huang

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Background: PLC-β signaling is generally thought to be mediated by allosteric activation by G proteins and Ca2+. Although availability of the phosphatidylinositol-4,5-biphosphate (PIP2) 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. Results: Using diacylglycerol-stimulated TRPC6 and inositol trisphosphate-mediated Ca2+ transients as cellular biosensors, we show that WNK1 stimulates PLC-β signaling in cells by promoting the synthesis of PIP2 via stimulation of phosphatidylinositol 4-kinase IIIα. WNK1 kinase activity is not required. Stimulation of PLC-β by WNK1 and by Gαq are synergistic; WNK1 activity is essential for regulation of PLC-β signaling by Gq-coupled receptors, and basal input from Gq is necessary for WNK1 signaling via PLC-β. WNK1 further amplifies PLC-β signaling when it is phosphorylated by Akt kinase in response to insulin-like growth factor. Conclusions: WNK1 is a novel regulator of PLC-β that acts by controlling substrate availability. WNK1 thereby coordinates signaling between G protein and Akt kinase pathways. Because PIP2 is itself a signaling molecule, regulation of PIP2 synthesis by WNK1 also allows the cell to initiate PLC signaling while independently controlling the effects of PIP2 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 PIP2 availability.

Original languageEnglish (US)
Pages (from-to)1979-1987
Number of pages9
JournalCurrent Biology
Volume21
Issue number23
DOIs
StatePublished - Dec 6 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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