Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1
Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1
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DOI：
10.1073/pnas.93.25.14665
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发表时间：
1996-12-10
影响因子：
11.1
通讯作者：
Bernstein, A
中科院分区：
文献类型：
--
作者：
Piao, XH;Paulson, R;Bernstein, A
在啮齿动物和人肥大细胞白血病中已经鉴定了Kit受体酪氨酸激酶的激活突变。一种激活Kit突变在密码子816处用缬氨酸取代天冬氨酸（D816 V），并且经常在人肥大细胞增多症中观察到。在鼠c-kit基因的等同位置处的突变，涉及酪氨酸取代天冬氨酸（D814 Y），已经在小鼠肥大细胞瘤细胞系P815中描述。我们已经研究了这种突变的致癌激活机制，这种突变的Kit受体酪氨酸激酶在肥大细胞系中的表达导致130-kDa蛋白的选择性酪氨酸磷酸化和65-kDa磷蛋白通过泛素依赖性蛋白水解途径的降解，该65-kDa蛋白被鉴定为含有src同源结构域2（SH 2）的蛋白酪氨酸磷酸酶SHP-1，其是Kit和其他造血受体的信号传导的负调节剂，和鼠蛾化基因座的蛋白质产物。这种突变也改变了受体自磷酸化和肽底物选择性的网站。因此，这种突变通过一种新的机制激活Kit的致癌潜力，该机制涉及Kit底物识别的改变和SHP-1（Kit信号传导途径的衰减剂）的降解。
Activating mutations in the Kit receptor tyrosine kinase have been identified in both rodent and human mast cell leukemia, One activating Kit mutation substitutes a valine for aspartic acid at codon 816 (D816V) and is frequently observed in human mastocytosis, Mutation at the equivalent position in the murine c-kit gene, involving a substitution of tyrosine for aspartic acid (D814Y), has been described in the mouse mastocytoma cell line P815. We have investigated the mechanism of oncogenic activation by this mutation, Expression of this mutant Kit receptor tyrosine kinase in a mast cell line led to the selective tyrosine phosphorylation of a 130-kDa protein and the degradation, through the ubiquitin-dependent proteolytic pathway, of a 65-kDa phosphoprotein, The 65-kDa protein was identified as the src homology domain 2 (SH2)-containing protein tyrosine phosphatase SHP-1, a negative regulator of signaling by Kit and other hematopoietic receptors, and the protein product of the murine motheaten locus. This mutation also altered the sites of receptor autophosphorylation and peptide substrate selectivity. Thus, this mutation activates the oncogenic potential of Kit by a novel mechanism involving an alteration in Kit substrate recognition and the degradation of SHP-1, an attenuator of the Kit signaling pathway.