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Papers In Press, published online ahead of print January 27, 2005
Department of Neuroscience, Karolinska Institute, Stockholm 17177
Corresponding Author: carlos.ibanez{at}neuro.ki.se
Alternative splicing of transcripts encoding the RET kinase receptor leads to isoforms differing in their cytoplasmic tail. Although in vitro studies have demonstrated a higher transforming activity of the long RET isoform (RET51), only the short isoform (RET9) can rescue the effects of a RET null mutation in enteric nervous system and kidney development. The molecular basis underlying the distinct functions of the two RET isoforms is not understood. Here we demonstrate that activated RET51 associates more strongly with the ubiquitin ligase Cbl than RET9, leading to increased ubiquitylation and faster turnover of RET51. The association of Cbl with RET is indirect and is mediated through Grb2. A constitutive complex of Grb2 and Cbl can be recruited to both receptor isoforms via docking of Shc to phosphorylated Tyr-1062 in RET. A mutant Shc protein unable to recruit the Grb2-Cbl complex decreases the turnover and prolongs the half-life of RET9, thus ascribing a previously unknown negative role to the Shc adaptor molecule. In addition, phosphorylation of Tyr-1096, which is present in RET51 but absent in RET9, endows the longer isoform with a second route to recruit the Grb2/Cbl complex. These findings establish a mechanism for the differential downregulation of RET9 and RET51 signaling which could explain the apparently paradoxical activities of these two RET isoforms. More generally, these results illustrate how alternative splicing can regulate the half-life and function of a growth factor receptor.
J. Biol. Chem, 10.1074/jbc.M500507200
Submitted on January 14, 2005
Revised on January 27, 2005
Accepted on January 27, 2005
Distinct turnover of alternatively-spliced isoforms of the RET kinase receptor mediated by differential recruitment of the Cbl ubiquitin ligase
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