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The noncatalytic TrkCNC2 receptor is cleaved by metalloproteases upon neurotrophin-3 stimulation

Oncogene volume 22, pages 740–745 (2003)Cite this article

Abstract

The trkC locus encodes catalytic and noncatalytic receptors, generated by alternative splicing. These primary high-affinity neurotrophin-3 (NT-3) receptors may act in concert to modulate responsiveness to NT-3. Signal modulation can also be achieved by receptors that are post-translationally processed. We report that the noncatalytic TrkC receptor, TrkCNC2, is cleaved at the membrane-proximal region of its extracellular domain. This generates a soluble ectodomain (gp90TrkCNC2) recovered in the cell culture medium and a membrane-bound fragment (p20TrkCNC2), which contains the transmembrane and intracellular regions including the juxtamembrane and the NC2-specific cytoplasmic domains. We also show that this processing, which does not occur in the TrkC catalytic counterpart, is upregulated by NT-3 and upon treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Moreover, cleavage inhibition after EDTA or 1.10 phenanthroline treatment suggests involvement of a metalloprotease(s). Finally, this post-translational processing was observed not only in TrkCNC2-overexpressing NIH3T3 cells but also in primary cultures of cortical neurons and brain extracts. This study shows that, in addition to alternative splicing, ectodomain shedding represents a novel means of regulating TrkC receptor signaling, and consequently NT-3 biological effects on target cells.

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Acknowledgements

This work was funded by the Institut Curie, the Centre National de la Recherche Scientifique and by a grant from the Association pour la Recherche sur le Cancer to F.L. (no. 9802). S Mateos was supported by a fellowship from the French Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche.

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  1. Institut Curie, CNRS UMR 146, Centre Universitaire, Orsay Cedex, 91405, France

    Stéphanie Mateos, Georges Calothy & Fabienne Lamballe

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  1. Stéphanie Mateos
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  2. Georges Calothy
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  3. Fabienne Lamballe
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Correspondence to Fabienne Lamballe.

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Mateos, S., Calothy, G. & Lamballe, F. The noncatalytic TrkCNC2 receptor is cleaved by metalloproteases upon neurotrophin-3 stimulation. Oncogene 22, 740–745 (2003). https://doi.org/10.1038/sj.onc.1206213

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