Trafficking Regulator of GLUT4-1 (TRARG1) is a GSK3 Substrate

Overview

Journal Biochem J

Specialty Biochemistry

Date 2022 May 20

PMID 35594055

Authors

Xiaowen Duan

Dougall M Norris

Sean J Humphrey

Pengyi Yang

Kristen C Cooke

Will P Bultitude

Benjamin L Parker

Olivia J Conway

James G Burchfield

James R Krycer

Frances M Brodsky

David E James

Daniel J Fazakerley

Affiliations

Soon will be listed here.

Abstract

Trafficking regulator of GLUT4-1, TRARG1, positively regulates insulin-stimulated GLUT4 trafficking and insulin sensitivity. However, the mechanism(s) by which this occurs remain(s) unclear. Using biochemical and mass spectrometry analyses we found that TRARG1 is dephosphorylated in response to insulin in a PI3K/Akt-dependent manner and is a novel substrate for GSK3. Priming phosphorylation of murine TRARG1 at serine 84 allows for GSK3-directed phosphorylation at serines 72, 76 and 80. A similar pattern of phosphorylation was observed in human TRARG1, suggesting that our findings are translatable to human TRARG1. Pharmacological inhibition of GSK3 increased cell surface GLUT4 in cells stimulated with a submaximal insulin dose, and this was impaired following Trarg1 knockdown, suggesting that TRARG1 acts as a GSK3-mediated regulator in GLUT4 trafficking. These data place TRARG1 within the insulin signaling network and provide insights into how GSK3 regulates GLUT4 trafficking in adipocytes.

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