Key Publications

Discovery of the iRhoms, key regulators of ADAM17 (collaboration with Prof. Tak Mak and Dr. David McIlwain, Univ. of Toronto)

 
 

  • McIlwain, D.R. et al. 2012.   iRhom2 regulates innate immunity via TACE/ADAM17. Science 335:229-32

  • Maretzky, T. et al. 2013. iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding.  Proc. Natl. Acad. Sci. U S A. 110(28):11433-8

  • Li X. et al. 2015. iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling. Proc. Natl. Acad. Sci. U S A. 112(19):6080-5.

  • Li, X. et al. 2017.  Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis. J Cell Sci. 130(5):868-878. doi: 10.1242/jcs.196436

  • Weskamp G. et al., 2020. ADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1). J Biol Chem. Mar 27;295(13):4350-4358.

  • Tang B. et al. 2020. Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains. FASEB J. Apr;34(4):4956-4969.

  • Zhao, Y. et al., 2022. Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17. Int. J. Mol. Sci. Oct 24;23(21):12796

  • Rabinowitsch, A.I. et al., 2023. Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice. J Cell Sci. Jul 1;136(13):jcs260910.

Translational relevance of iRhom2/ADAM17

 
 

  • Issuree, P.A. et al. 2013. Novel role for IRHOM2 in the pathogenesis of inflammatory arthritis. J. Clin. Inv. 123(2):928-32

  • Qing X. et al. 2018. iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling. J Clin Invest. 128(4):1397-1412.

  • Haxaire C., et al. 2018. Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNFα pathway. Blood 132(10):1064-1074

Function and regulation of ADAM17 as principal sheddase for EGFR-ligands and TNFa.

 

  • Sahin, U. et al., 2004. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR-ligands. J. Cell Biol. 164:769-779.

  • Blobel, C.P. 2005. ADAMs: key components in EGFR signalling and development Nature Reviews Mol. Cell. Bio. 6:32-43.

  • Horiuchi, K. et al. 2007. TNFa-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock.  J. Imm. 179:2686-2689

  • Le Gall, S.M. et al. 2010. ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site. J. Cell Science. 23(Pt 22):3913-22

  • Franzke, C.W. et al. 2012. Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation. J. Exp. Med. 4;209(6):1105-19.

  • Lora, J. et al. 2021. Targeted truncation of the ADAM17 cytoplasmic domain in mice results in protein destabilization and a hylomorphic phenotype. J. Biol. Chem. Jan-Jun;296:100733.