A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome.
A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome.
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DOI：
10.1016/j.molcel.2015.04.015
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发表时间：
2015-06-04
期刊：
影响因子：
16
通讯作者：
Wang, Richard C.
中科院分区：
文献类型：
--
作者：
Lee, Eunice E.;Ma, Jing;Sacharidou, Anastasia;Mi, Wentao;Salato, Valerie K.;Nam Nguyen;Jiang, Youxing;Pascual, Juan M.;North, Paula E.;Shaul, Philip W.;Mettlen, Marcel;Wang, Richard C.
蛋白激酶C与红细胞/脑葡萄糖转运蛋白GLUT 1的磷酸化有关，但对磷酸化位点和对葡萄糖转运的可能影响还没有明确的认识。通过体外激酶测定，质谱和磷酸化特异性抗体，我们确定丝氨酸226 GLUT 1作为PKC磷酸化位点。S226的磷酸化是葡萄糖摄取的快速增加和由佛波酯12-O-十四烷酰基-佛波醇-13-乙酸酯（TPA）诱导的GLUT 1的增强的细胞表面定位所必需的。内源性GLUT 1磷酸化的S226在原代内皮细胞响应TPA或VEGF。几种自然发生的致病性突变导致GLUT 1缺乏综合征，破坏这种PKC磷酸化，损害体外S226的磷酸化，并阻断TPA介导的葡萄糖摄取增加。我们证明了GLUT 1在S226上的磷酸化调节葡萄糖转运，并提出这种修饰在葡萄糖转运的生理调节中是重要的。
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.
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