The neurotensin (NT) receptor-3/sortilin (NTR3) belongs to the new receptor family of VPS10P domain containing receptors. The NTR3 is expressed in all cancer cells on which NT activates cell growth and its cellular location is mainly intracellular within the endoplasmic reticulum and the trans-Golgi network. However, the NTR3 is also present at the cell surface of the HT29 cell line from which it is released by a mechanism activated by phorbol 12-myristate 13-acetate (PMA). The shedding of the NTR3 is sensitive to protein kinase C (PKC) and mitogen-activated protein (MAP) kinase inhibitors and to 1,10-phenanthroline and BB3103, suggesting the activation of zinc-metalloproteases and the ADAM10 (a desintegrin and metalloprotease). The shedding of the membrane NTR3 leads to a soluble protein able to bind exogenous NT, suggesting a role of this process in the biological activity of the peptide. (C) 2002 Elsevier Science (USA). All rights reserved.