A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome

Eunice E. Lee, Jing Ma, Anastasia Sacharidou, Wentao Mi, Valerie K. Salato, Nam Nguyen, Youxing Jiang, Juan M. Pascual, Paula E. North, Philip W. Shaul, Marcel Mettlen, Richard C. Wang

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Abstract

Protein kinase C has been implicated in the phosphorylation of the erythrocyte/brain glucose transporter, GLUT1, without a clear understanding of the site(s) of phosphorylation and the possible effects on glucose transport. Through invitro kinase assays, mass spectrometry, and phosphospecific antibodies, we identify serine 226 in GLUT1 as a PKC phosphorylation site. Phosphorylation of S226 is required for the rapid increase in glucose uptake and enhanced cell surface localization of GLUT1 induced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Endogenous GLUT1 is phosphorylated on S226 in primary endothelial cells in response to TPA or VEGF. Several naturally occurring, pathogenic mutations that cause GLUT1 deficiency syndrome disrupt this PKC phosphomotif, impair the phosphorylation of S226 invitro, and block TPA-mediated increases in glucose uptake. We demonstrate that the phosphorylation of GLUT1 on S226 regulates glucose transport and propose that this modification is important in the physiological regulation of glucose transport. The functional significance of GLUT1 phosphorylation by PKC is unclear. Lee etal. identify a phosphorylation site, demonstrate its essential role in the rapid induction of glucose uptake, and find that its phosphorylation is impaired by mutations that cause GLUT1 deficiency syndrome.

Original languageEnglish (US)
JournalMolecular Cell
DOIs
StateAccepted/In press - Nov 24 2014

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Protein Kinase C
Phosphorylation
Glucose
Acetates
Glucose Transporter Type 1
Phospho-Specific Antibodies
Glut1 Deficiency Syndrome
Mutation
Phorbol Esters
Tetradecanoylphorbol Acetate
Serine
Vascular Endothelial Growth Factor A
Mass Spectrometry
Phosphotransferases
Endothelial Cells
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome. / Lee, Eunice E.; Ma, Jing; Sacharidou, Anastasia; Mi, Wentao; Salato, Valerie K.; Nguyen, Nam; Jiang, Youxing; Pascual, Juan M.; North, Paula E.; Shaul, Philip W.; Mettlen, Marcel; Wang, Richard C.

In: Molecular Cell, 24.11.2014.

Research output: Contribution to journalArticle

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