CATALYTIC SPECIFICITY OF PROTEIN-TYROSINE KINASES IS CRITICAL FOR SELECTIVE SIGNALING
CATALYTIC SPECIFICITY OF PROTEIN-TYROSINE KINASES IS CRITICAL FOR SELECTIVE SIGNALING
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DOI：
10.1038/373536a0
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发表时间：
1995-02-09
期刊：
影响因子：
64.8
通讯作者：
CANTLEY, LC
中科院分区：
文献类型：
--
作者：
SONGYANG, Z;CARRAWAY, KL;CANTLEY, LC
不同的蛋白酪氨酸激酶如何激活特定的下游事件？酪氨酸激酶或酪氨酸激酶靶点上的Src-同源性-2（SH 2）结构域识别特定序列背景下的磷酸酪氨酸，从而提供一定的特异性（1-3）。酪氨酸激酶的催化位点在确定靶特异性中的作用尚未得到充分研究。在这里，我们使用一个简并肽库，以显示每个九个酪氨酸激酶的调查有一个独特的最佳肽底物。我们发现胞质酪氨酸激酶优先磷酸化由其自身的SH 2结构域或密切相关的SH 2结构域识别的肽（I组;参考文献3），而受体酪氨酸激酶优先磷酸化由I组的SH 2结构域亚组识别的肽（3）。我们观察到RET受体型酪氨酸激酶的点突变导致多发性内分泌腺瘤2B型，导致肽底物特异性的转变，这强调了这些发现对人类疾病的重要性。
How do distinct protein-tyrosine kinases activate specific downstream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence context and thereby provide some specificity(1-3). The role of the catalytic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate. We find that the cytosolic tyrosine kinases preferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor tyrosine kinases preferentially phosphorylate peptides recognized by subsets of group In SH2 domains(3). The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrate specificity.