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

Mol Cell. 2015 Jun 4;58(5):845-53. doi: 10.1016/j.molcel.2015.04.015. Epub 2015 May 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Glucose Transporter Type 1
  • Monosaccharide Transport Proteins
  • SLC2A1 protein, human
  • PRKCA protein, human
  • Protein Kinase C-alpha
  • Glucose

Supplementary concepts

  • Glut1 Deficiency Syndrome