2. Academic Validation
  3. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

  • Science. 2018 Dec 7;362(6419):1177-1182. doi: 10.1126/science.aap7607.
M Steklov # 1 2,  S Pandolfi # 1 2,  M F Baietti # 1 2,  A Batiuk 1 2,  P Carai 3,  P Najm 1 2,  M Zhang 4,  H Jang 4,  F Renzi 1 2,  Y Cai 1 2,  L Abbasi Asbagh 1 2,  T Pastor 1 2,  M De Troyer 1 2,  M Simicek 1 2,  E Radaelli 5,  H Brems 5,  E Legius 5,  J Tavernier 6 7,  K Gevaert 6 7,  F Impens 8,  L Messiaen 5 9,  R Nussinov 4 10,  S Heymans 3 11 12,  S Eyckerman 6 7,  A A Sablina 13 2
Affiliations

Affiliations

  • 1 VIB-KU Leuven Center for Cancer Biology, VIB, 3000 Leuven, Belgium.
  • 2 Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
  • 3 Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
  • 4 Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
  • 5 Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
  • 6 VIB Medical Biotechnology Center, Albert Baertsoenkaai 3, 9000 Ghent, Belgium.
  • 7 Department of Biochemistry, Ghent University, Albert Baertsoenkaai 3, 9000 Ghent, Belgium.
  • 8 VIB Proteomics Core, Albert Baertsoenkaai 3, 9000 Ghent, Belgium.
  • 9 Department of Genetics, University of Alabama, Birmingham, AL 35294, USA.
  • 10 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • 11 Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Netherlands.
  • 12 The Netherlands Heart Institute, Nl-HI, Utrecht, Netherlands.
  • 13 VIB-KU Leuven Center for Cancer Biology, VIB, 3000 Leuven, Belgium. [email protected].
  • # Contributed equally.
PMID: 30442762 DOI: 10.1126/science.aap7607
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 Lztr1 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 Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-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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