Ectodomain shedding of human Nogo-66 receptor homologue-1 by zinc metalloproteinases.
The Nogo-66 receptor (NgR) plays a pivotal role in the inhibition of neuroregeneration as the receptor for multiple neurite outgrowth inhibitors such as Nogo-A. We have previously shown that NgR undergoes zinc metalloproteinase-mediated ectodomain shedding in neuroblastoma cells. Here, we demonstrate that the NgR-related protein NgR homologue-1 is released from neuroblastoma cells as a full-length ectodomain (NgRH1-ecto) and an N-terminal fragment (NTF-NgRH1) containing the leucine-rich repeat region of the protein. Inhibitors of the major protease classes failed to block the release of NgRH1-ecto, suggesting that this occurs via a protease-independent mechanism, presumably by a phospholipase-like enzyme. The release of NTF-NgRH1 was blocked by a hydroxamate-based zinc metalloproteinase inhibitor and tissue inhibitor of metalloproteinases-2 and -3, but not -1, implicating the involvement of membrane-type matrix metalloproteinases in this process. Our findings thus highlight the parallels between the ectodomain shedding of NgRH1 and that previously described for NgR.
Walmsley
Adrian R
AR
Neuroscience research, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. adrian_robert.walmsley@pharma.novartis.com
Mir
Anis K
AK
Frentzel
Stefan
S
D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070817:Nogo Receptor 2; D010446:Peptide Fragments / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism*
D058851:GPI-Linked Proteins; D000070817:Nogo Receptor 2; D010446:Peptide Fragments; D011480:Protease Inhibitors; C474327:RTN4RL2 protein, human; D011956:Receptors, Cell Surface; D019714:Tissue Inhibitor of Metalloproteinases; D045726:Metalloproteases; D015032:Zinc