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Phosphorylation of iRhom2 Is Essential for Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE

43 Pages Posted: 10 Apr 2018 Publication Status: Published

See all articles by Miguel Cavadas

Miguel Cavadas

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Ioanna Oikonomidi

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Emma Burbridge

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Catarina Gaspar

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Marina Badenes

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Tianyi Hu

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Alfonso Bolado

University of Edinburgh - Edinburgh Cancer Research UK Centre

Christopher Gerner

University of Vienna - Institute of Analytical Chemistry

Alex von Kriegsheim

University of Edinburgh - Edinburgh Cancer Research UK Centre

Colin Adrain

Fundação Calouste Gulbenkian - Membrane Traffic Lab

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Abstract

Cell surface metalloproteases coordinate signaling during development, tissue homeostasis and disease. TACE (TNFa Converting Enzyme), is the metalloprotease responsible for proteolytic release, ('shedding'), of membrane-tethered signaling molecules including the cytokine TNF, and activating ligands of the EGFR. A key step in TACE biogenesis involves its interaction with iRhom2, controlling TACE trafficking from the ER to the trans-Golgi network. Another important, but mechanistically unclear, feature of TACE biology is its ability to be rapidly stimulated on the cell surface, by numerous agents. Here we report a novel role for cell surface iRhom2 in TACE stimulation. Stimuli that provoke TACE shedding trigger iRhom2 phosphorylation within its cytoplasmic tail, dependent on MAP kinases. Blocking iRhom2 phosphorylation does not affect TACE trafficking, but impairs the shedding of TACE substrates, through defective proteolytic activity. Our data suggest that shedding stimuli utilize an 'inside out' signaling mechanism, transducing cytoplasmic signals through iRhom2, engaging TACE sheddase activity.

Suggested Citation

Cavadas, Miguel and Oikonomidi, Ioanna and Burbridge, Emma and Gaspar, Catarina and Badenes, Marina and Hu, Tianyi and Bolado, Alfonso and Gerner, Christopher and von Kriegsheim, Alex and Adrain, Colin, Phosphorylation of iRhom2 Is Essential for Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE (2018). Available at SSRN: https://ssrn.com/abstract=3155647 or http://dx.doi.org/10.2139/ssrn.3155647
This version of the paper has not been formally peer reviewed.

Miguel Cavadas

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Oeiras
Portugal

Ioanna Oikonomidi

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Oeiras
Portugal

Emma Burbridge

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Oeiras
Portugal

Catarina Gaspar

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Oeiras
Portugal

Marina Badenes

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Oeiras
Portugal

Tianyi Hu

Fundação Calouste Gulbenkian - Membrane Traffic Lab

Oeiras
Portugal

Alfonso Bolado

University of Edinburgh - Edinburgh Cancer Research UK Centre

Edinburgh
United Kingdom

Christopher Gerner

University of Vienna - Institute of Analytical Chemistry

Austria

Alex Von Kriegsheim

University of Edinburgh - Edinburgh Cancer Research UK Centre

Edinburgh
United Kingdom

Colin Adrain (Contact Author)

Fundação Calouste Gulbenkian - Membrane Traffic Lab ( email )

Oeiras
Portugal

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