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Signaling by TrkA and TrkB receptor tyrosine kinase is required for peripheral neuron survival. TrkA and TrkB signaling is facilitated by the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor superfamily, through mechanisms that remain obscure. Here, we demonstrate that TrkA and TrkB induces MEKdependent phosphorylation of the transmembrane cysteine protease ADAM17 (a disintegrin and metalloprotease 17) at the intracellular residue threonine 735. Phosphorylation at this site activates ADAM17 and causes cleavage of p75NTR and production of the receptors’ intracellular domain (p75NTR^ICD) in PC12 cells and in primary cerebellar granule neurons. We show that Trkinduced ADAM17 phosphorylation and generation of the p75NTR is required for neurotrophininduced Erk and Akt activation and for neurotrophindependent survival signaling. Survival of PC12 …