Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

Debora Degl'Innocenti, Elena Arighi, Anna Popsueva, Romina Sangregorio, Luisella Alberti, Maria Grazia Rizzetti, Cristina Ferrario, Hannu Sariola, Marco A. Pierotti, Maria Grazia Borrello

Research output: Contribution to journalArticlepeer-review

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 SKN-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.

Original languageEnglish
Pages (from-to)7297-7309
Number of pages13
JournalOncogene
Volume23
Issue number44
DOIs
Publication statusPublished - Sep 23 2004

Keywords

  • Cell branching
  • Cell scattering
  • Cell transformation
  • RET isoforms
  • Tyr1062

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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