Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability
Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability
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DOI：
10.1523/jneurosci.23-13-05425.2003
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发表时间：
2003-07-02
影响因子：
5.3
通讯作者：
Schecterson, LC
中科院分区：
文献类型：
--
作者：
Kanning, KC;Hudson, M;Schecterson, LC
75 kDa神经营养因子受体（p75（NTR））和两种神经营养因子受体同源物（NRH 1、NRH 2）构成神经生长因子/肿瘤坏死因子受体超家族的一个亚家族。NRH 1与p75（NTR）共存于鱼类、两栖动物和鸟类中，但在哺乳动物中不存在，而NRH 2仅存在于哺乳动物中。与p75（NTR）和NRH 1不同，NRH 2缺乏典型的细胞外配体结合结构域。NRH 2与金属蛋白酶切割p75（NTR）的产物的相似性促使我们更详细地检查p75（NTR）的切割。p75（NTR）、NRH 1和NRH 2经历多次蛋白水解裂解，最终释放胞质片段。对于p75（NTR），PMA诱导的膜金属蛋白酶在胞外结构域中的切割之后是跨膜结构域内或附近的切割，将胞内结构域释放到细胞质中。这种加工类似于α-和γ-分泌酶介导的β-淀粉样前体蛋白的加工以及Notch的类似加工。虽然神经营养因子不调节p75（NTR）的加工，α-和γ-分泌酶介导的p75的切割是由受体酪氨酸激酶（Trks）TrkA和TrkB，但不是TrkC调节。令人惊讶的是，尽管NRH 1和NRH 2也经历胞内结构域的蛋白水解胞质释放，但不同的蛋白酶介导切割。此外，尽管p75（NTR）可溶性胞内结构域仅在蛋白酶体抑制剂存在下积累，但NRH 2的等效片段是稳定的并定位于细胞核中。由于可溶性胞内结构域的p75（NTR）和NRH 2被发现激活NF-κ B与TNF受体相关因子6（TRAF 6），我们建议，这些蛋白质的切割可能通过不同的蛋白酶保守的细胞质和细胞核的信号转导功能。
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 alpha- and gamma-secretase-mediated processing of beta-amyloid precursor protein and the similar processing of Notch. Although neurotrophins did not regulate p75(NTR) processing, the alpha- and gamma-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-kappaB 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.