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

Miguel Cavadas; Ioanna Oikonomidi; Catarina J Gaspar; Emma Burbridge; Marina Badenes; Inês Félix; Alfonso Bolado; Tianyi Hu; Andrea Bileck; Christopher Gerner; Pedro M Domingos; Alex von Kriegsheim; Colin Adrain

doi:10.1016/j.celrep.2017.09.074

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

Miguel Cavadas, Ioanna Oikonomidi, Catarina J Gaspar, Emma Burbridge, Marina Badenes, Inês Félix, Alfonso Bolado, Tianyi Hu, Andrea Bileck, Christopher Gerner, Pedro M Domingos, Alex von Kriegsheim, Colin Adrain

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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.

Original language	English
Pages (from-to)	745-757
Number of pages	13
Journal	Cell Reports
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2017.09.074
Publication status	Published - 17 Oct 2017
Externally published	Yes

Bibliographical note

Keywords

14-3-3 Proteins/metabolism
ADAM17 Protein/metabolism
Animals
Carrier Proteins/chemistry
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

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10.1016/j.celrep.2017.09.074Licence: CC BY

Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease
Copyright the authors 2017. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Final published version, 2.88 MBLicence: CC BY

Colin Adrain
- C.Adrainqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Senior Lecturer
- Patrick G Johnston Centre for Cancer Research
Person: Academic

Cite this

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title = "Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE",

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.",

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author = "Miguel Cavadas and Ioanna Oikonomidi and Gaspar, {Catarina J} and Emma Burbridge and Marina Badenes and In{\^e}s F{\'e}lix and Alfonso Bolado and Tianyi Hu and Andrea Bileck and Christopher Gerner and Domingos, {Pedro M} and {von Kriegsheim}, Alex and Colin Adrain",

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AU - Cavadas, Miguel

AU - Oikonomidi, Ioanna

AU - Gaspar, Catarina J

AU - Burbridge, Emma

AU - Badenes, Marina

AU - Félix, Inês

AU - Bolado, Alfonso

AU - Hu, Tianyi

AU - Bileck, Andrea

AU - Gerner, Christopher

AU - Domingos, Pedro M

AU - von Kriegsheim, Alex

AU - Adrain, Colin

PY - 2017/10/17

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N2 - 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.

AB - 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.

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KW - Carrier Proteins/chemistry

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KW - Endoplasmic Reticulum/metabolism

KW - HEK293 Cells

KW - Humans

KW - Mice, Knockout

KW - Mitogen-Activated Protein Kinases/metabolism

KW - Phosphorylation

KW - Phosphoserine/metabolism

KW - Proteolysis

KW - Signal Transduction

KW - Substrate Specificity

KW - Toll-Like Receptors/metabolism

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SN - 2211-1247

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JO - Cell Reports

JF - Cell Reports

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ER -

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

Abstract

Bibliographical note

Keywords

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Colin Adrain

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