GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation

Isao Usui, Takeshi Imamura, Hiroaki Satoh, Jie Huang, Jennie Bever, Christopher J. Hupfeld, Jerrold M. Olefsky

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

G protein-coupled receptor kinases (GRKs) represent a class of proteins that classically phosphorylate agonist-activated G protein-coupled receptors, leading to uncoupling of the receptor from further G protein activation. Recently, we have reported that the heterotrimeric G protein α-subunit, Gαq/11, can mediate insulin-stimulated glucose transport. GRK2 contains a regulator of G protein signaling (RGS) domain with specificity for Gαq/11. Therefore, we postulated that GRK2 could be an inhibitor of the insulin signaling cascade leading to glucose transport in 3T3-L1 adipocytes. In this study, we demonstrate that microinjection of anti-GRK2 antibody or siRNA against GRK2 increased insulin-stimulated insulin-responsive glucose transporter 4 (GLUT4) translocation, while adenovirus-mediated overexpression of wild-type or kinase-deficient GRK2 inhibited insulin-stimulated GLUT4 translocation as well as 2-deoxyglucose uptake. Importantly, a mutant GRK2 lacking the RGS domain was without effect. Taken together, these results indicate that through its RGS domain endogenous GRK2 functions as a negative regulator of insulin-stimulated glucose transport by interfering with Gαq/11 signaling to GLUT4 translocation. Furthermore, inhibitors of GRK2 can lead to enhanced insulin sensitivity.

Original languageEnglish (US)
Pages (from-to)2821-2829
Number of pages9
JournalEMBO Journal
Volume23
Issue number14
DOIs
StatePublished - Jul 21 2004
Externally publishedYes

Fingerprint

GTP-Binding Proteins
GTP-Binding Protein Regulators
Insulin
Glucose
Facilitative Glucose Transport Proteins
Proteins
G-Protein-Coupled Receptor Kinases
Glucose Transporter Type 4
Heterotrimeric GTP-Binding Proteins
Deoxyglucose
Protein Subunits
Microinjections
G-Protein-Coupled Receptors
Adipocytes
Adenoviridae
Small Interfering RNA
Insulin Resistance
Anti-Idiotypic Antibodies
Phosphotransferases
Chemical activation

Keywords

  • Gαq/11
  • GLUT4 translocation
  • GRK2
  • Insulin signal transduction

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Usui, I., Imamura, T., Satoh, H., Huang, J., Bever, J., Hupfeld, C. J., & Olefsky, J. M. (2004). GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. EMBO Journal, 23(14), 2821-2829. https://doi.org/10.1038/sj.emboj.7600297

GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. / Usui, Isao; Imamura, Takeshi; Satoh, Hiroaki; Huang, Jie; Bever, Jennie; Hupfeld, Christopher J.; Olefsky, Jerrold M.

In: EMBO Journal, Vol. 23, No. 14, 21.07.2004, p. 2821-2829.

Research output: Contribution to journalArticle

Usui, I, Imamura, T, Satoh, H, Huang, J, Bever, J, Hupfeld, CJ & Olefsky, JM 2004, 'GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation', EMBO Journal, vol. 23, no. 14, pp. 2821-2829. https://doi.org/10.1038/sj.emboj.7600297
Usui, Isao ; Imamura, Takeshi ; Satoh, Hiroaki ; Huang, Jie ; Bever, Jennie ; Hupfeld, Christopher J. ; Olefsky, Jerrold M. / GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. In: EMBO Journal. 2004 ; Vol. 23, No. 14. pp. 2821-2829.
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