The noncatalytic TrkCNC2 receptor is cleaved by metalloproteases upon neurotrophin-3 stimulation.
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 (gp90(TrkCNC2)) recovered in the cell culture medium and a membrane-bound fragment (p20(TrkCNC2)), 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.
Mateos
Stéphanie
S
Institut Curie, CNRS UMR 146, Centre Universitaire, Orsay, France.
Calothy
Georges
G
Lamballe
Fabienne
F
D016475:3T3 Cells; D000818:Animals; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D020933:Neurotrophin 3 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*
D020933:Neurotrophin 3; D020812:Receptor, trkC; D008666:Metalloendopeptidases