alpha-secretase (ADAM17) is a metalloprotese that has the ability to cleave the p75NTR extracellular domain, in proximity of the transmembrane region. The cleaved extracellular domain is shed from the cell membrane, whereas the rest of the protein, the C-terminal fragment, stays anchored to the membrane. The released extracellular domain represents a binding protein for many potential ligands, including neurotrophins, pro-neurotrophin precursors, beta-amyloid. Shedding of the p75NTR extracellular region can be both constituve and stimulated. The constitutive shedding is dependent on signalling via the p38 MAP kinase. Shedding can be stimulated by the phorbol ester PMA, acting through protein kinase C and ERK activation, and by a tyrosine phosphatase inhibitor. Activation of TRKA by NGF (or TRKB by BDNF) also induces release of the p75NTR extracellular domain. The alpha-secretase cleavage is required for the subsequent cleavage by gamma-secretase.
Zampieri, N, Xu, CF, Chao, MV, Neubert, TA
Petrova, K, Kim, DS, Murray, S, Jung, KM, Kim, TW, Kim, PK, Landman, N, Tan, S, Ryu, SH, Lewis, R, Chao, MV
Amieux, PS, Schecterson, LC, Wiley, JC, Hudson, M, Kanning, KC, Bothwell, M
metallopeptidase activity of p-S,T-ADAM17(215-827):Zn2+ [plasma membrane]
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