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首页> 外文期刊>Molecular and Cellular Biology >The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase Cgamma.
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The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase Cgamma.

机译：Ret / ptc2的全部致癌活性取决于酪氨酸539，酪氨酸539是磷脂酶Cgamma的停靠位点。

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RET/PTC oncogenes, generated by chromosomal rearrangements in papillary thyroid carcinomas, are constitutively activated versions of proto-RET, a gene coding for a receptor-type tyrosine kinase (TK) whose ligand is still unknown. RET/PTCs encode fusion proteins in which proto-RET TK and C-terminal domains are fused to different donor genes. The respective Ret/ptc oncoproteins display constitutive TK activity and tyrosine phosphorylation. We found that Ret/ptcs associate with and phosphorylate the SH2-containing transducer phospholipase Cgamma (PLCgamma). Two putative PLCgamma docking sites, Tyr-505 and Tyr-539, have been identified on Ret/ptc2 by competition experiments using phosphorylated peptides modelled on Ret sequence. Transfection experiments and biochemical analysis using Tyr-->Phe mutants of Ret/ptc2 allowed us to rule out Tyr-505 and to identify Tyr-539 as a functional PLCgamma docking site in vivo. Moreover, kinetic measurements showed that Tyr-539 is able to mediate high-affinity interaction with PLCgamma. Mutation of Tyr-539 resulted in a drastically reduced oncogenic activity of Ret/ptc2 on NIH 3T3 cells (75 to 90% reduction) both in vitro and in vivo, which correlates with impaired ability of Ret/ptc2 to activate PLCgamma. In conclusion, this paper demonstrates that Tyr-539 of Ret/ptc2 (Tyr-761 on the proto-RET product) is an essential docking site for the full transforming potential of the oncogene. In addition, the present data identify PLCgamma as a downstream effector of Ret/ptcs and suggest that this transducing molecule could play a crucial role in neoplastic signalling triggered by Ret/ptc oncoproteins.
机译：由甲状腺乳头状癌中的染色体重排产生的RET / PTC癌基因是proto-RET的组成型激活形式，proto-RET是一种编码受体型酪氨酸激酶（TK）的基因，其配体仍然未知。 RET / PTCs编码融合蛋白，其中原始RET TK和C端结构域与不同的供体基因融合。各自的Ret / ptc癌蛋白表现出组成型TK活性和酪氨酸磷酸化。我们发现Ret / ptcs与含SH2的换能器磷脂酶Cgamma（PLCgamma）缔合并磷酸化。通过使用模拟在Ret序列上的磷酸化肽段进行竞争实验，在Ret / ptc2上确定了两个推定的PLCgamma停靠位点Tyr-505和Tyr-539。使用Ret / ptc2的Tyr-> Phe突变体进行转染实验和生化分析，使我们可以排除Tyr-505并将Tyr-539鉴定为体内功能性PLCgamma停靠位点。此外，动力学测量表明，Tyr-539能够介导与PLCgamma的高亲和力相互作用。 Tyr-539的突变导致Ret / ptc2对NIH 3T3细胞的致癌活性大大降低（降低了75％至90％），这与Ret / ptc2激活PLCgamma的能力受损有关。总之，本文证明了Ret / ptc2的Tyr-539（原RET产品上的Tyr-761）是致癌基因完全转化潜力的重要停靠位点。此外，目前的数据确定PLCgamma是Ret / ptcs的下游效应子，并表明该转导分子可能在Ret / ptc癌蛋白触发的肿瘤信号传导中起关键作用。

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