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

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

Author information

1
Membrane Traffic Lab, Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal.
2
Membrane Traffic Lab, Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Oeiras, Portugal.
3
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
4
Institut für Analytische Chemie, Universität Wien, Währinger Strasse 38, 1090 Vienna, Austria.
5
Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Oeiras, Portugal.
6
Membrane Traffic Lab, Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal. Electronic address: cadrain@igc.gulbenkian.pt.

Abstract

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

PMID:
29045841
PMCID:
PMC5656746
DOI:
10.1016/j.celrep.2017.09.074
[Indexed for MEDLINE]
Free PMC Article

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