PRODUCT OF VAV PROTOONCOGENE DEFINES A NEW CLASS OF TYROSINE PROTEIN-KINASE SUBSTRATES
PRODUCT OF VAV PROTOONCOGENE DEFINES A NEW CLASS OF TYROSINE PROTEIN-KINASE SUBSTRATES
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DOI：
10.1038/356068a0
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发表时间：
1992-03-05
期刊：
影响因子：
64.8
通讯作者：
BARBACID, M
中科院分区：
文献类型：
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作者：
BUSTELO, XR;LEDBETTER, JA;BARBACID, M
一些参与细胞对有丝分裂刺激反应调节的蛋白质含有一个共同的非催化结构域SH2 (src-同源结构域2)，该结构域介导它们与活化的酪氨酸蛋白激酶的相互作用。在这里，我们报道了p95vav，一种在造血系统细胞中特异性表达的原癌基因产物，包含一个SH2结构域，是酪氨酸蛋白激酶的底物。将异位表达p95vav的静止NIH3T3细胞暴露于表皮或血小板来源的生长因子中，可诱导该蛋白在酪氨酸残基上的快速磷酸化。这些生长因子的受体被其同源配体激活，导致它们与p95vav结合，这是一个由其SH2结构域介导的过程。在T细胞中，T细胞受体和辅助性CD4细胞表面蛋白的共同激活也会导致酪氨酸残基中内源性p95vav蛋白的磷酸化。p95vav的磷酸化是快速的，短暂的，在大多数其他含磷酸酪氨酸蛋白出现之前。除了SH2结构域外，p95vav还含有其他酪氨酸激酶底物中没有的结构基序。其中一个基序是螺旋-环-螺旋/亮氨酸拉链状结构域，它与Myc和Max蛋白中的这些基序具有一定的序列相似性。螺旋-环-螺旋样基序的缺失导致p95vav的致癌激活。这些结果表明p95vav是一种新型的信号转导分子，并提示该蛋白可能在酪氨酸磷酸化信号转导到转录事件中的作用。
SEVERAL proteins implicated in the regulation of cellular responses to mitogenic stimuli contain a common non-catalytic domain, SH2 (for src-homologous domain 2), that mediates their interaction with activated tyrosine protein kinases. Here we report that p95vav, a proto-oncogene product specifically expressed in cells of the haematopoietic system, contains an SH2 domain and is a substrate for tyrosine protein kinases. Exposure of quiescent NIH3T3 cells ectopically expressing p95vav to either epidermal or platelet-derived growth factors induces the rapid phosphorylation of this protein on tyrosine residues. Activation of the receptors for these growth factors by their cognate ligand results in their association with p95vav, a process mediated by its SH2 domain. In T cells, co-activation of the T-cell receptor and the accessory CD4 cell-surface protein also results in the phosphorylation of the endogenous p95vav protein in tyrosine residues. Phosphorylation of p95vav is rapid, transient and precedes the appearance of most other phosphotyrosine-containing proteins. In addition to the SH2 domain, p95vav contains structural motifs not found in other tyrosine kinase substrates. One such motif is a helix-loop-helix/leucine zipper-like domain which shares some sequence similarity with these motifs in the Myc and Max proteins. Deletion of the helix-loop-helix-like motif causes oncogenic activation of p95vav. These results indicate that p95vav is a new type of signal transduction molecule and suggest a possible role for this protein in the transduction of tyrosine phosphorylation signalling into transcriptional events.