Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching
Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching
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RET 同种型对 Tyr1062 多对接位点的不同需求促进神经细胞分散和上皮细胞分支
DOI：
10.1038/sj.onc.1207862
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发表时间：
2004
期刊：
影响因子：
8
通讯作者：
M. Borrello
中科院分区：
文献类型：
--
作者：
D. Degl'innocenti;E. Arighi;A. Popsueva;R. Sangregorio;L. Alberti;M. G. Rizzetti;C. Ferrario;H. Sariola;M. Pierotti;M. Borrello
受体酪氨酸激酶RET选择性剪接产生两种主要亚型，RET 9和RET 51，其羧基末端不同。激活的RET诱导不同的生物学反应，例如形态转化、神经突生长、增殖、细胞迁移和分支。这两种亚型在小鼠发育中具有不同的细胞内信号传导途径和不同的作用。在这里，我们表明，这两种异构体都能够诱导SK-N-MC神经上皮瘤细胞系的细胞分散和MDCK细胞系中的分支小管形成。然而，Y1062F突变，消除了转化活性的激活RET亚型在NIH3T3细胞中，不消除散射和分支形态发生的RET 51，而削弱了这些生物学效应的RET 9。GDNF诱导的RET51的生物学效应通过同时废除Tyr1062和Tyr1096对接位点而被抑制。因此，Tyr1096可能取代Tyr1062的功能。GRB 2是唯一已知的与Tyr1096结合的衔接蛋白。MDCK细胞中表达的显性阴性GRB 2与RET 9或RET 51一起显著减少分支。因此，GRB 2是RET介导的MDCK细胞分支所必需的。
The receptor tyrosine kinase RET is alternatively spliced to yield two main isoforms, RET9 and RET51, which differ in their carboxyl terminal. Activated RET induces different biological responses such as morphological transformation, neurite outgrowth, proliferation, cell migration and branching. The two isoforms have been suggested to have separate intracellular signaling pathways and different roles in mouse development. Here we show that both isoforms are able to induce cell scattering of SK-N-MC neuroepithelioma cell line and branching tubule formation in MDCK cell line. However, the Y1062F mutation, which abrogates the transforming activity of both activated RET isoforms in NIH3T3 cells, does not abolish scattering and branching morphogenesis of RET51, whereas impairs these biological effects of RET9. The GDNF-induced biological effects of RET51 are inhibited by the simultaneous abrogation of both Tyr1062 and Tyr1096 docking sites. Thus, Tyr1096 may substitute the functions of Tyr1062. GRB2 is the only known adaptor protein binding to Tyr1096. Dominant-negative GRB2 expressed in MDCK cells together with RET9 or RET51 significantly reduces branching. Therefore, GRB2 is necessary for RET-mediated branching of MDCK cells.