ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha. Academic Article uri icon

Overview

abstract

  • Protein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-alpha, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)-alpha and heparin-binding epidermal growth factor, but Ca++ influx activated an additional sheddase for these epidermal growth factor receptor ligands in Adam17-/- cells. Here, we show that Ca++ influx and stimulation of the P2X7R signaling pathway activate ADAM10 as sheddase of many ADAM17 substrates in Adam17-/- fibroblasts and primary B cells. Importantly, although ADAM10 can shed all substrates of ADAM17 tested here in Adam17-/- cells, acute treatment of wild-type cells with a highly selective ADAM17 inhibitor (SP26) showed that ADAM17 is nevertheless the principal sheddase when both ADAMs 10 and 17 are present. However, chronic treatment of wild-type cells with SP26 promoted processing of ADAM17 substrates by ADAM10, thus generating conditions such as in Adam17-/- cells. These results have general implications for understanding the substrate selectivity of two major cellular sheddases, ADAMs 10 and 17.

publication date

  • January 21, 2009

Research

keywords

  • ADAM Proteins
  • Amyloid Precursor Protein Secretases
  • L-Selectin
  • Membrane Proteins
  • Transforming Growth Factor alpha
  • Tumor Necrosis Factor-alpha

Identity

PubMed Central ID

  • PMC2655247

Scopus Document Identifier

  • 65249090883

Digital Object Identifier (DOI)

  • 10.1091/mbc.e08-11-1135

PubMed ID

  • 19158376

Additional Document Info

volume

  • 20

issue

  • 6