Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth
Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth
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DOI：
10.1073/pnas.95.24.14379
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发表时间：
1998-11-24
影响因子：
11.1
通讯作者：
Comoglio, PM
中科院分区：
文献类型：
--
作者：
Bardelli, A;Longati, P;Comoglio, PM
编码酪氨酸激酶受体的基因可能在人类癌症中发挥作用的假设已经被RET和KIT激酶结构域的致癌突变的鉴定所证实。最近，在乳头状肾癌（PRCs）中发现了MET的同源残基突变。这些遗传病变与细胞转化之间的联系尚不清楚。METPRC突变导致激酶活性增加，在某些情况下，如M1250T取代，底物特异性改变。METPRC突变体的转化潜能与其通过位于受体尾部的两个磷酸化酪氨酸(Y（1349)VHVNATY(1356)VNV）组成性结合信号转导的能力之间存在直接关联。用苯丙氨酸取代这些“对接酪氨酸”不会改变激酶的性质，但在体外消除了转化和侵袭性。用酪氨酸磷酸化肽衍生物((YVNV)-V-p将受体与信号转导解偶联可抑制METPRC突变体诱导的侵袭性生长。这些数据表明，组成受体与下游信号转导的偶联是由突变MET驱动的肿瘤转化的关键机制，并建议针对与该癌基因相关的肿瘤疾病的治疗策略。
The assumption that genes encoding tyrosine kinase receptors could play a role in human cancers has been confirmed by the identification of oncogenic mutations in the kinase domain of RET and KIT. Recently, homologous residues were found mutated in MET, in papillary renal carcinomas (PRCs). The link coupling these genetic lesions to cellular transformation is still unclear. METPRC mutations result in increased kinase activity and-in some instances, i.e., M1250T substitution-in changes in substrate specificity, A direct correlation occurs between the transforming potential of METPRC mutants and their ability to constitutively associate with signal transducers through two phosphorylated tyrosines (Y(1349)VHVNATY(1356)VNV) located in the receptor tail. Substitution of these "docking tyrosines" with phenylalanines leaves unaffected the altered properties of the kinase but abrogates transformation and invasiveness in vitro. Uncoupling the receptor from signal transducers with a tyrosine-phosphorylated peptide derivative ((YVNV)-V-p) inhibits invasive growth induced by METPRC mutants. These data indicate that constitutive receptor coupling to downstream signal transducers is a key mechanism in neoplastic transformation driven by mutated MET and suggest a therapeutic strategy to target neoplastic diseases associated with this oncogene.