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J. Biol. Chem., Vol. 280, Issue 14, 13442-13449, April 8, 2005

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Distinct Turnover of Alternatively Spliced Isoforms of the RET Kinase Receptor Mediated by Differential Recruitment of the Cbl Ubiquitin Ligase^*

Rizaldy P. Scott, Susanna Eketjäll, Helena Aineskog, and Carlos F. Ibáñez¶

From the Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, S-17177 Stockholm, Sweden

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 the enteric nervous system and kidney development. The molecular basis underlying the distinct functions of the two RET isoforms is not understood. Here we demonstrated that activated RET51 associated more strongly with the ubiquitin ligase Cbl than did RET9, leading to increased ubiquitylation and faster turnover of RET51. The association of Cbl with RET was indirect and was mediated through Grb2. A constitutive complex of Grb2 and Cbl could 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 decreased the turnover and prolonged 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, endowed the longer isoform with a second route to recruit the Grb2·Cbl complex. These findings establish a mechanism for the differential down-regulation of RET9 and RET51 signaling that 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.

Received for publication, January 14, 2005

^* This work was supported by the Swedish Foundation for Strategic Research, by Grant 3474-B97-05XBC from the Swedish Cancer Society, by Grant QLG3-CT-2002-01000 from the Vth Framework Program of the European Union, and by the Karolinska Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Present address: Samuel Lunenfeld Research Inst., Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

^¶ To whom correspondence should be addressed: Division of Molecular Neurobiology, Dept. of Neuroscience, Karolinska Inst., Retzius väg 8, S-17177 Stockholm, Sweden. Tel.: 46-8-5248-7660; Fax: 46-8-33-95-48; E-mail: carlos.ibanez{at}neuro.ki.se.

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