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iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding

Maretzky, Thorsten ; Mcllwain, David R. ; Issuree, Priya Darshinee A. ; Li, Xue ; Malapeira, Jordi ; Amin, Sadaf ; Lang, Philipp A. ; Mak, Tak W. ; Blobel, Carl P.

Proceedings of the National Academy of Sciences - PNAS, 2013-07, Vol.110 (28), p.11433-11438 [Periódico revisado por pares]

United States: National Academy of Sciences

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  • Título:
    iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding
  • Autor: Maretzky, Thorsten ; Mcllwain, David R. ; Issuree, Priya Darshinee A. ; Li, Xue ; Malapeira, Jordi ; Amin, Sadaf ; Lang, Philipp A. ; Mak, Tak W. ; Blobel, Carl P.
  • Assuntos: ADAM Proteins - physiology ; ADAM17 Protein ; Animals ; Antibodies ; Binding sites ; Biochemistry ; Biological Sciences ; Carrier Proteins - genetics ; Carrier Proteins - physiology ; Cells, Cultured ; Chimeras ; Crosstalk ; Cytoplasm ; Keratinocytes ; Ligands ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid cells ; Phosphorylation ; Physiological regulation ; Proteins ; Quantification ; Signal transduction ; Small interfering RNA ; Substrate Specificity ; TNF inhibitors
  • É parte de: Proceedings of the National Academy of Sciences - PNAS, 2013-07, Vol.110 (28), p.11433-11438
  • Notas: http://dx.doi.org/10.1073/pnas.1302553110
    ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    Author contributions: T.M., D.R.M., P.D.A.I., X.L., J.M., S.A., P.A.L., and C.P.B. designed research; T.M., D.R.M., P.D.A.I., X.L., J.M., S.A., and P.A.L. performed research; T.M., D.R.M., P.D.A.I., X.L., J.M., S.A., P.A.L., and T.W.M. contributed new reagents/analytic tools; T.M., D.R.M., P.D.A.I., X.L., S.A., P.A.L., and C.P.B. analyzed data; and T.M., D.R.M., P.D.A.I., and C.P.B. wrote the paper.
    Edited* by Harvey F. Lodish, Whitehead Institute for Biomedical Research, Cambridge, MA, and approved June 3, 2013 (received for review February 7, 2013)
  • Descrição: Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNFα release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17. Mature ADAM17 is present in mouse embryonic fibroblasts (mEFs) lacking iRhom2, and yet ADAM17 is unable to support stimulated shedding of several of its substrates, including heparin-binding EGF and Kit ligand 2 in this context. Stimulated shedding of other ADAM17 substrates, such as TGFα, is not affected in iRhom 2 ⁻/⁻ mEFs but can be strongly reduced by treating iRhom2 ⁻/⁻ mEFs with siRNA against iRhom1. Activation of heparin-binding EGF or Kit ligand 2 shedding by ADAM17 in iRhom2 ⁻/⁻ mEFs can be rescued by wild-type iRhom2 but not by iRhom2 lacking its N-terminal cytoplasmic domain. The requirement for the cytoplasmic domain of iRhom2 for stimulated shedding by ADAM17 may help explain why the cytoplasmic domain of ADAM17 is not required for stimulated shedding. The functional relevance of iRhom2 in regulating shedding of EGF receptor (EGFR) ligands is established by a lack of lysophasphatidic acid/ADAM17/EGFR-dependent crosstalk with ERK1/2 in iRhom2 ⁻/⁻ mEFs, and a significant reduction of FGF7/ADAM17/EGFR-stimulated migration of iRhom2 ⁻/⁻ keratinocytes. Taken together, these findings uncover functions for iRhom2 in the regulation of EGFR signaling and in controlling the activation and substrate selectivity of ADAM17-dependent shedding events.
  • Editor: United States: National Academy of Sciences
  • Idioma: Inglês
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