Abstract
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.
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Acknowledgements
We gratefully acknowledge Mordechai Anafi and Bruce J Mayer for the GRB2 constructs, Darrin P Smith for RET-MEN2A mutant constructs and Cinzia Lanzi for RPI1 inhibitor. We thank Miss Maria Teresa Radice for excellent technical assistance and Miss Cristina Mazzadi for secretarial help. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and Consiglio Nazionale Ricerche (CNR).
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Degl'Innocenti, D., Arighi, E., Popsueva, A. et al. Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching. Oncogene 23, 7297–7309 (2004). https://doi.org/10.1038/sj.onc.1207862
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DOI: https://doi.org/10.1038/sj.onc.1207862
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