Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE

Cell Rep. 2017 Oct 17;21(3):745-757. doi: 10.1016/j.celrep.2017.09.074.


Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.

Keywords: 14-3-3; ADAM metalloproteases; ADAM17/TACE; EGFR; MAP kinases; TNF; ectodomain shedding; iRhom2.

MeSH terms

  • 14-3-3 Proteins / metabolism
  • ADAM17 Protein / metabolism*
  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cell Membrane / metabolism
  • Endoplasmic Reticulum / metabolism
  • HEK293 Cells
  • Humans
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism
  • Proteolysis*
  • Signal Transduction
  • Substrate Specificity
  • Toll-Like Receptors / metabolism


  • 14-3-3 Proteins
  • Carrier Proteins
  • Toll-Like Receptors
  • iRhom2 protein, mouse
  • Phosphoserine
  • Mitogen-Activated Protein Kinases
  • ADAM17 Protein