Cleavage of the TrkA neurotrophin receptor by multiple metalloproteases generates signalling-competent truncated forms

The ectodomain of the neurotrophin receptor TrkA has been recovered as a so luble fragment from the culture media of cells by a process that involves e ndoproteolytic cleavage. This cleavage may be upregulated by several treatm ents, including NGF treatment or protein kinase C activation. In this repor t we have investigated the cellular site and proteolytic activities involve d in TrkA cleavage, and the effects of ectodomain truncation on signalling. Cleavage occurs when the receptor is at, or near, the cell surface, and it can be prevented by agents that affect protein sorting. Cleavage generates several cell-bound fragments, and their generation can be differentially b locked by inhibitors, documenting the involvement of multiple plasma membra ne metalloendoproteases. The major cell-bound receptor fragment (i) is tyro sine-phosphorylated in vivo; (ii) does autophosphorylate in vitro; and (iii ) is able to associate with intracellular signalling substrates. Artificial deletion of the TrkA ectodomain results in an active receptor that induced neurite outgrowth in pheochromocytoma cells. Cleavage by this natural cell ular mechanism appears thus to serve not only as an outlet of receptor bind ing fragments, but also to generate signalling-competent cell-bound recepto r fragments. In the nervous system this ligand-independent receptor activat ion could play important roles in the development and survival of neurons.