Disruption of TACE-filamin interaction can inhibit TACE-mediated ectodomain shedding

Biochem Biophys Res Commun. 2017 Aug 26;490(3):997-1003. doi: 10.1016/j.bbrc.2017.06.153. Epub 2017 Jun 27.

Abstract

Ectodomain shedding regulates functions of many membrane proteins through the cleavage of their juxtamembrane region mainly by a disintegrin and metalloproteinase family proteinases. Tumor necrosis factor-alpha converting enzyme (TACE) is known to be responsible for phorbol myristate acetate (PMA)-induced shedding of various membrane proteins. How PMA regulates TACE-dependent shedding and how TACE exhibits substrate specificity without proteolysis of other membrane proteins are questionable. Here, we show that TACE can interact with an actin-binding protein, filamin, through 20th filamin repeat. We found that the interaction between TACE and filamin was increased by PMA treatment. In addition, loss of filamin or specific disruption of TACE-filamin interaction inhibited ectodomain shedding of representative TACE substrates, CD44 and amyloid protein precursor. From these data, we suggest that filamin may work as a scaffold that can recruit TACE and its substrates in a PMA-dependent manner to achieve substrate specificity for TACE.

Keywords: Ectodomain shedding; Epithin; Filamin; PMA; TACE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / analysis
  • ADAM17 Protein / metabolism*
  • Carcinogens / metabolism*
  • Cell Line, Tumor
  • Filamins / analysis
  • Filamins / metabolism*
  • Humans
  • Models, Molecular
  • Protein Domains / drug effects
  • Protein Interaction Maps / drug effects
  • Serine Endopeptidases / analysis
  • Serine Endopeptidases / metabolism*
  • Tetradecanoylphorbol Acetate / metabolism*

Substances

  • Carcinogens
  • Filamins
  • Serine Endopeptidases
  • ST14 protein, human
  • ADAM17 Protein
  • ADAM17 protein, human
  • Tetradecanoylphorbol Acetate