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

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

http://hdl.handle.net/10400.7/794

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Abstract(s)

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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Keywords

ADAM metalloproteases ADAM17/TACE iRhom2 14-3-3 MAP kinases TNF EGFR ectodomain shedding

URI

http://hdl.handle.net/10400.7/794

Citation

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, Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE, In Cell Reports, Volume 21, Issue 3, 2017, Pages 745-757, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2017.09.074. (http://www.sciencedirect.com/science/article/pii/S2211124717313797) Keywords: ADAM metalloproteases; ADAM17/TACE; iRhom2; 14-3-3; MAP kinases; TNF; EGFR; ectodomain shedding