WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

Zhizeng Sun; Alan V Smrcka; Songhai Chen

doi:10.1074/jbc.M113.462564

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WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

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WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

Zhizeng Sun, Alan V Smrcka and Songhai Chen

The Journal of biological chemistry, Vol.288(23), pp.16715-16725

06/07/2013

DOI: 10.1074/jbc.M113.462564

PMCID: PMC3675605

PMID: 23625927

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Abstract

Background: It remains unclear how Gβγ regulates diverse effectors in cells. Results: WDR26 exists in oligomers. It simultaneously binds both Gβγ and PLCβ2 to enhance PLCβ2 membrane translocation and activation by Gβγ in leukocytes. Conclusion: WDR26 functions as a scaffolding protein to promote Gβγ-mediated PLCβ2 activation. Significance: These findings uncover a novel mechanism of regulating Gβγ signaling through a scaffolding protein. We have recently identified WDR26 as a novel WD40 repeat protein that binds Gβγ and promotes Gβγ signaling during leukocyte migration. Here, we have determined the mechanism by which WDR26 enhances Gβγ-mediated phospholipase C β2 (PLCβ2) activation in leukocytes. We show that WDR26 not only directly bound Gβγ but also PLCβ2. The binding sites of WDR26 and PLCβ2 on Gβ 1 γ 2 were overlapping but not identical. WDR26 used the same domains for binding Gβγ and PLCβ but still formed a signaling complex with Gβγ and PLCβ2 probably due to the fact that WDR26 formed a higher order oligomer through its Lis homology and C-terminal to LisH (LisH-CTLH) and WD40 domains. Additional studies indicated that the formation of higher order oligomers was required for WDR26 to promote PLCβ2 interaction with and activation by Gβγ. Moreover, WDR26 was required for PLCβ2 translocation from the cytosol to the membrane in polarized leukocytes, and the translocation of PLCβ2 was sufficient to cause partial activation of PLCβ2. Collectively, our data indicate that WDR26 functions as a scaffolding protein to promote PLCβ2 membrane translocation and interaction with Gβγ, thereby enhancing PLCβ2 activation in leukocytes. These findings have identified a novel mechanism of regulating Gβγ signaling through a scaffolding protein.

Phosphatidylinositol

G Protein-coupled Receptors (GPCR)

WDR26

Signal Transduction

Heterotrimeric G Proteins

G Protein βγ

WD40 Repeat Proteins

Chemotaxis

Phospholipase C

Details

Title: Subtitle: WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes
Creators: Zhizeng Sun - From the Departments of
Alan V Smrcka - the
Songhai Chen - From the Departments of
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(23), pp.16715-16725
DOI: 10.1074/jbc.M113.462564
PMID: 23625927
PMCID: PMC3675605
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: GM094255 / National Institutes of Health
Alternative title: WDR26 Scaffolds PLCβ2 Activation by Gβγ
Language: English
Date published: 06/07/2013
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040342602771

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