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

Gisela Weskamp, Johannes Schlöndorff, Lawrence Lum, J. David Becherer, Tae Wan Kim, Paul Saftig, Dieter Hartmann, Gillian Murphy, Carl P. Blobel

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

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 p75 NTR, 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.

Original languageEnglish (US)
Pages (from-to)4241-4249
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number6
DOIs
StatePublished - Feb 6 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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