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Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

  1. Author:
    Steklov, M.
    Pandolf, S.
    Baietti, M. F.
    Batiuk, A.
    Carai, P.
    Najm, P.
    Zhang,Mingzhen
    Jang,Hyunbum
    Renzi, F.
    Cai, Y.
    Asbagh, L. Abbasi
    Pastor, T.
    De Troyer, M.
    Simicek, M.
    Radaelli, E.
    Brems, H.
    Legius, E.
    Tavernier, J.
    Gevaert, K.
    Impens, F.
    Messiaen, L.
    Nussinov, R.
    Heymans, S.
    Eyekerman, S.
    Sablina, A. A.

  2. Author Address

    Katholieke Univ Leuven, Ctr Canc Biol, VIB, B-3000 Leuven, Belgium.Katholieke Univ Leuven, Dept Oncol, Herestr 49, B-3000 Leuven, Belgium.Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Herestr 49, B-3000 Leuven, Belgium.NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.Katholieke Univ Leuven, Dept Human Genet, Herestr 49, B-3000 Leuven, Belgium.VIB Med Biotechnol Ctr, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.Univ Ghent, Dept Biochem, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.VIB Prote Core, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA.Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel.Maastricht Univ, Fac Hlth Med & Life Sci, Dept Cardiol, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands.Netherlands Heart Inst, NI HI, Utrecht, Netherlands.
    1. Year: 2018
    2. Date: Dec 7
    3. Epub Date: 2018 11 15
  2. Journal: Science (New York, N.Y.)
  3. AMER ASSOC ADVANCEMENT SCIENCE,
    1. 362
    2. 6419
    3. Pages: 1177-1182
  5. Type of Article: Article
  6. ISSN: 0036-8075
  1. Abstract:

    The leucine zipper-like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztrl haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

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External Sources

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  2. DOI: 10.1126/science.aap7607
  3. PMID: 30442762
  4. View record in Web of Science®
  5. WOS: 000452506300060

Library Notes

  1. Fiscal Year: FY2018-2019
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