Interaction between O-GlcNAc modification and tyrosine phosphorylation of prohibitin: implication for a novel binary switch.
Interaction between O-GlcNAc modification and tyrosine phosphorylation of prohibitin: implication for a novel binary switch.
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DOI：
10.1371/journal.pone.0004586
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Mishra, Suresh
中科院分区：
文献类型：
--
作者：
Ande, Sudharsana R.;Moulik, Saby;Mishra, Suresh
抑制素（Prohibitin，简称PHB或PHB 1）是一种进化上保守的多功能蛋白质，存在于包括质膜在内的多种细胞区室中。然而，涉及的各种功能的机制尚未完全探讨。在这里，我们首次报道了PHB与O-连接的β-N-乙酰葡糖胺转移酶（O-GlcNAc转移酶，OGT）相互作用，并被O-GlcNAc修饰;并且也经历了响应胰岛素的酪氨酸磷酸化。PHB中的酪氨酸114（Tyr 114）和酪氨酸259（Tyr 259）分别紧邻潜在的O-GlcNAc位点丝氨酸121（Ser 121）和苏氨酸258（Thr 258）。通过定点突变用苯丙氨酸取代PHB中的Tyr 114和Tyr 259残基导致减少的酪氨酸磷酸化以及减少的O-GlcNAc修饰的PHB。令人惊讶的是，这也导致增强的酪氨酸磷酸化和OGT活性。这是由于在PHB和OGT中存在相似的酪氨酸基序。Ser 121和Thr 258分别用丙氨酸和异亮氨酸取代导致O-GlcNAc修饰的减弱和PHB的酪氨酸磷酸化的增加，表明这两种动态修饰之间的关联。具有已知O-GlcNAc修饰位点或已知酪氨酸磷酸化位点的O-GlcNAc修饰蛋白的序列分析揭示了各种蛋白中这两种翻译后修饰之间的强潜在关联。我们推测O-GlcNAc修饰和酪氨酸磷酸化在酪氨酸激酶信号通路包括胰岛素、生长因子和免疫受体信号通路中起重要作用。此外，我们提出，O-GlcNAc修饰和酪氨酸磷酸化是一种新的以前未识别的二元开关，这可能会提供新的机制的见解细胞信号通路，并开放直接实验检查。
Prohibitin (PHB or PHB1) is an evolutionarily conserved, multifunctional protein which is present in various cellular compartments including the plasma membrane. However, mechanisms involved in various functions of PHB are not fully explored yet. Here we report for the first time that PHB interacts with O-linked β-N-acetylglucosamine transferase (O-GlcNAc transferase, OGT) and is O-GlcNAc modified; and also undergoes tyrosine phosphorylation in response to insulin. Tyrosine 114 (Tyr114) and tyrosine 259 (Tyr259) in PHB are in the close proximity of potential O-GlcNAc sites serine 121 (Ser121) and threonine 258 (Thr258) respectively. Substitution of Tyr114 and Tyr259 residues in PHB with phenylalanine by site-directed mutagenesis results in reduced tyrosine phosphorylation as well as reduced O-GlcNAc modification of PHB. Surprisingly, this also resulted in enhanced tyrosine phosphorylation and activity of OGT. This is attributed to the presence of similar tyrosine motifs in PHB and OGT. Substitution of Ser121 and Thr258 with alanine and isoleucine respectively resulted in attenuation of O-GlcNAc modification and increased tyrosine phosphorylation of PHB suggesting an association between these two dynamic modifications. Sequence analysis of O-GlcNAc modified proteins having known O-GlcNAc modification site(s) or known tyrosine phosphorylation site(s) revealed a strong potential association between these two posttranslational modifications in various proteins. We speculate that O-GlcNAc modification and tyrosine phosphorylation of PHB play an important role in tyrosine kinase signaling pathways including insulin, growth factors and immune receptors signaling. In addition, we propose that O-GlcNAc modification and tyrosine phosphorylation is a novel previously unidentified binary switch which may provide new mechanistic insights into cell signaling pathways and is open for direct experimental examination.
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10.1111/j.1582-4934.2006.tb00404.x
发表时间：
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影响因子：
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