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The Journal of Neuroscience, July 2, 2003, 23(13):5425-5436

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Proteolytic Processing of the p75 Neurotrophin Receptor and Two Homologs Generates C-Terminal Fragments with Signaling Capability

Kevin C. Kanning,^1,3 Mark Hudson,¹ Paul S. Amieux,² Jesse C. Wiley,^1,4 Mark Bothwell,¹ and Leslayann C. Schecterson¹

Departments of ¹Physiology and Biophysics and ²Pharmacology, ³Neurobiology and Behavior Graduate Program, and ⁴Molecular and Cell Biology Graduate Program, University of Washington, Seattle, Washington 98195

The 75 kDa neurotrophin receptor (p75^NTR) and two neurotrophin receptor homologs (NRH1, NRH2) constitute a subfamily of the nerve growth factor/tumor necrosis factor receptor superfamily. NRH1 coexists with p75^NTR in fish, amphibians, and birds but is absent in mammals, whereas NRH2 exists only in mammals. Unlike p75^NTR and NRH1, NRH2 lacks a canonical extracellular ligand binding domain. The similarity of NRH2 to the product of metalloproteinase cleavage of p75^NTR prompted us to examine the cleavage of p75^NTR in greater detail. p75^NTR, NRH1, and NRH2 undergo multiple proteolytic cleavages that ultimately release cytoplasmic fragments. For p75^NTR, cleavage in the extracellular domain by a PMA-inducible membrane metalloproteinase is followed by cleavage within or near the transmembrane domain, releasing the intracellular domain into the cytoplasm. This processing resembles the - and -secretase-mediated processing of -amyloid precursor protein and the similar processing of Notch. Although neurotrophins did not regulate p75^NTR processing, the- and-secretase-mediated cleavage of p75 is modulated by receptor tyrosine kinases (Trks) TrkA and TrkB but not TrkC. Surprisingly, although NRH1 and NRH2 also undergo proteolytic cytoplasmic release of intracellular domains, a different protease mediates the cleavage. Furthermore, whereas the p75^NTR soluble intracellular domain accumulates only in the presence of proteasome inhibitors, the equivalent fragment of NRH2 is stable and localizes in the nucleus. Because soluble intracellular domains of p75^NTR and NRH2 were found to activate NF-B in concert with TNF receptor associated factor 6 (TRAF6), we propose that cleavage of these proteins may serve conserved cytoplasmic and nuclear signaling functions through distinct proteases.

Key words: proteolysis; p75^NTR; neurotrophin; Trk; regulated intramembrane proteolysis; RIP; NF-B

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Received Nov. 25, 2002; revised Apr. 17, 2003; accepted Apr. 24, 2003.

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