Identification of Shc docking site on Ret tyrosine kinase
Identification of Shc docking site on Ret tyrosine kinase
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DOI：
10.1038/sj.onc.1200896
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发表时间：
1997-02-20
期刊：
影响因子：
8
通讯作者：
Borrello, MG
中科院分区：
文献类型：
--
作者：
Arighi, E;Alberti, L;Borrello, MG
RET原癌基因编码在神经嵴和肾脏发育中起作用的受体型酪氨酸激酶的两种亚型，RET的不同种系突变与遗传性癌症综合征MEN2A， MEN2B FMTC以及先天性先天性巨结肠病（HSCR）相关，而在甲状腺乳头状癌中经常检测到体细胞重排（RET/ ptc）。在这项研究中，我们已经证明了转导接头分子She可以被RET亚型、重排的细胞质RET /ptc2癌蛋白以及被MEN2A或MEN2B相关突变激活的膜结合受体招募和激活。此外，我们的分析已经确定了Ret酪氨酸残基和She结构域参与相互作用，事实上，我们在这里发现She、PTB和SH2的磷酸酪氨酸结合结构域在体外都与Ret/ptc2相互作用，然而，PTB结构域结合Ret/ptc2的量比SH2高20倍，SH2和PTB结构域的推定结合位点都被确定为Ret/ptc2的Tyr586（原Ret上的Tyr1062）。与这一发现一致，通过使用RET/PTC2-Y586F突变体，我们已经证明了这个酪氨酸残基是两个RET亚型分化前的最后一个氨基酸，是She的对接位点。
The RET proto-oncogene encodes two isoforms of a receptor type tyrosine kinase which plays a role in neural crest and kidney development, Distinct germ-line mutations of RET have been associated inherited cancer syndromes MEN2A, MEN2B FMTC as well as with the congenital disorder Hirschsprung disease (HSCR), whereas somatic rearrangements (RET/PTCs) have been frequently detected in the papillary thyroid carcinoma, Despite these findings, suggesting a relevant role for RET product in development and neoplastic processes, little is known about the signalling triggered by this receptor, In this study, we have demonstrated that the transducing adaptor molecule She is recruited and activated by both Ret isoforms and by the rearranged cytoplasmatic Ret/ptc2 oncoproteins as well as by the membrane bound receptor activated by MEN2A or by MEN2B associated mutations, Moreover, our analysis has identified the Ret tyrosine residue and the She domains involved in the interaction, In fact, here we show that both the phosphotyrosine binding domains of She, PTB and SH2, interact with Ret/ptc2 in vitro, However, PTB domain binds 20 folds higher amount of Ret/ptc2 than SH2, The putative binding site for either SH2 and PTB domains has been identified as Tyr586 of Ret/ptc2 (Tyr1062 on proto-Ret). In keeping with this finding, by using RET/PTC2-Y586F mutant, we have demonstrated that this tyrosine residue, the last amino acid but one before the divergence of the two Ret isoforms, is the docking site for She.