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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.

Molecular cell, 2015-06, Vol.58 (5), p.845-853 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome
Autor: 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.
Assuntos: Amino Acid Sequence ; Animals ; Biological Transport ; Carbohydrate Metabolism, Inborn Errors - enzymology ; Carbohydrate Metabolism, Inborn Errors - genetics ; Cell Line ; Endothelial Cells - metabolism ; Erythrocytes - metabolism ; Glucose - metabolism ; Glucose Transporter Type 1 - genetics ; Glucose Transporter Type 1 - metabolism ; HeLa Cells ; Humans ; Molecular Sequence Data ; Monosaccharide Transport Proteins - deficiency ; Monosaccharide Transport Proteins - genetics ; Mutation, Missense ; Phosphorylation ; Protein Kinase C-alpha - physiology ; Protein Processing, Post-Translational ; Rats ; Xenopus laevis
É parte de: Molecular cell, 2015-06, Vol.58 (5), p.845-853
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SourceType-Scholarly Journals-1
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content type line 23
J.M. performed and analyzed experiments involving GLUT1 biochemistry and phosphorylation, including mass spectrometry. E.L. performed and analyzed glucose uptake studies, biotin labeling, and Xenopus oocyte experiments with assistance from R.W. W.M. performed oocyte injections with assistance from E.L. M.M. performed imaging experiments with assistance from R.W. A.S. and P.S. performed and analyzed most endothelial cell experiments with assistance from E.L. V.S. and P.N. performed and analyzed immunohistochemistry experiments. N.N. and Y.J. provided structural guidance and figures. J.P. enrolled volunteers and revised the manuscript. R.W. designed the project, analyzed experiments, and wrote the manuscript with contributions from E.L. and J.M.
Equal contribution
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Descrição: 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 in vitro 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 in vitro, 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. [Display omitted] •PKC phosphorylates GLUT1 on S226 in vitro and in vivo in endothelial cells•TPA-induced, rapid increases in glucose uptake require S226 phosphorylation•Phosphorylation of S226 increases GLUT1 membrane localization•Some GLUT1 deficiency syndrome mutations show impaired S226 phosphorylation The functional significance of GLUT1 phosphorylation by PKC is unclear. Lee et al. 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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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.

United States: Elsevier Inc

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