Journal article
WNK1 Promotes PIP2 Synthesis to Coordinate Growth Factor and GPCR-G(q) Signaling
Current biology, Vol.21(23), pp.1979-1987
12/06/2011
DOI: 10.1016/j.cub.2011.11.002
PMCID: PMC3237931
PMID: 22119528
Abstract
Background: PLC-beta 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-beta signaling in cells by promoting the synthesis of PIP2 via stimulation of phosphatidylinositol 4-kinase III alpha. WNK1 kinase activity is not required. Stimulation of PLC-beta by WNK1 and by G alpha(q) are synergistic; WNK1 activity is essential for regulation of PLC-beta signaling by G(q)-coupled receptors, and basal input from G(q) is necessary for WNK1 signaling via PLC-beta. WNK1 further amplifies PLC-beta signaling when it is phosphorylated by Akt kinase in response to insulin-like growth factor.
Conclusions: WNK1 is a novel regulator of PLC-beta 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.
Details
- Title: Subtitle
- WNK1 Promotes PIP2 Synthesis to Coordinate Growth Factor and GPCR-G(q) Signaling
- Creators
- Sung-Wan An - The University of Texas Southwestern Medical CenterSeung-Kuy Cha - The University of Texas Southwestern Medical CenterJoonho Yoon - The University of Texas Southwestern Medical CenterSeungwoo Chang - The University of Texas Southwestern Medical CenterElliott M. Ross - The University of Texas Southwestern Medical CenterChou-Long Huang - The University of Texas Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- Current biology, Vol.21(23), pp.1979-1987
- Publisher
- Elsevier
- DOI
- 10.1016/j.cub.2011.11.002
- PMID
- 22119528
- PMCID
- PMC3237931
- ISSN
- 0960-9822
- eISSN
- 1879-0445
- Number of pages
- 9
- Grant note
- GM30355; DK59530; DK85726; DK-079328 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01DK059530 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Genzyme; Sanofi-Aventis; Genzyme Corporation I-0982 / Welch Foundation; The Welch Foundation R37GM030355 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 12/06/2011
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984359842902771
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