Evidence for a Critical Role of the Tumor Necrosis Factor α Convertase (TACE) in Ectodomain Shedding of the p75 Neurotrophin Receptor (p75NTR)*

By G. Weskamp, J. Schlöndorff, L. Lum, J. Becherer, Tae‐Wan Kim, P. Saftig, D. Hartmann, Gillian Murphy, C. Blobel. 2004

160 citations recorded by the source corpus.

Protein ectodomain shedding, the proteolytic release of the extracellullar domain of membrane-tethered proteins, can dramatically affect the function of cell surface receptors, growth factors, cytokines, and other proteins. In this study, we evaluated the activities involved in ectodomain shedding of p75NTR, a neurotrophin receptor with critical roles in neuronal differentiation and survival. p75NTR is shed in a variety of cell types, including dorsal root ganglia cells and PC12 cells. In Chinese hamster ovary cells, inhibitors of the MEK/ERK and p38 MAP kinase pathways uncovered distinct signaling pathways required for the constitutive and stimulated shedding of p75NTR. Stimulated p75NTR shedding is abrogated in M2 mutant Chinese hamster ovary cells that lack functional tumor necrosis factor-α converting enzyme (TACE, also referred to as ADAM17) and in cells isolated from adam17-/- mice, but not in cells from adam9/12/15-/- or adam10-/- mice. Stimulated p75NTR shedding is strongly reduced by deletion of 15 amino acid residues in its extracellular membrane-proximal stalk domain. However, similar to other shed proteins, point mutations and overlapping shorter deletions within this region have little or no effect on shedding. Because ectodomain shedding of p75NTR releases a soluble ectodomain and could also be a prerequisite for its regulated intramembrane proteolysis, these findings may have important implications for the functional regulation of p75NTR.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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In Molecular Biology

1. Mengcheng Shen
2. Z. Kassiri
3. Carlos Fernandez-Patron
4. Pu Zhang
5. Gillian Murphy
6. C. Blobel
7. R. Khalil

Citations in the corpus

• Metalloprotease‐disintegrin ADAM8: Expression analysis and targeted deletion in mice (2005, background): “…ligands of the EGF receptor (Peschon et al., 1998; Merlos-Suarez et al., 2001; Sunnarborg et al., 2002; Sahin et al., 2004), fractalkine (Garton et al., 2001), amyloid precursor protein (Buxbaum et al., 1998), p75 neurotrophin-receptor (Weskamp et al., 2004), and MUC1 (Thathiah et al., 2003).”
• ADAMs family and relatives in cardiovascular physiology and pathology. (2016, background): “However, ADAM17 has also been reported to cleave TNFα receptors, RI (p55) and RII (p75) [33,87], which would lead to an opposite outcome than the release of TNFα ligand.”
• ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking (2005, background): “The fundamental importance of this modification has also been addressed and highlighted in studies where the active ERKdependent TACE-mediated shedding of TrkA, TGF-α and p75 neurotrophin receptor have been demonstrated (DiazRodriguez et al., 2002; Weskamp et al., 2004).”