Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

doi:10.1126/science.aap7607

GSTDTAP > 地球科学

DOI	10.1126/science.aap7607
	Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination
	Steklov, M.1,2; Pandolf, S.1,2; Baietti, M. F.1,2; Batiuk, A.1,2; Carai, P.3; Najm, P.1,2; Zhang, M.4; Jang, H.4; Renzi, F.1,2; Cai, Y.1,2; Asbagh, L. Abbasi 1,2; Pastor, T.1,2; De Troyer, M.1,2; Simicek, M.1,2; Radaelli, E.5; Brems, H.5; Legius, E.5; Tavernier, J.6,7; Gevaert, K.6,7; Impens, F.8; Messiaen, L.5,9; Nussinov, R.4,10; Heymans, S.3,11,12; Eyekerman, S.6,7; Sablina, A. A.1,2
	2018-12-07
发表期刊	SCIENCE
ISSN	0036-8075
EISSN	1095-9203
出版年	2018
卷号	362 期号:6419 页码:1177-+
文章类型	Article
语种	英语
国家	Belgium; USA; Israel; Netherlands
英文摘要	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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000452506300060
WOS关键词	FAST INTERACTION REFINEMENT ; RARE VARIANTS ; MEMBRANE ; FIREDOCK ; REVEALS ; CHARMM
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/200254
专题	地球科学资源环境科学气候变化
作者单位	1.Katholieke Univ Leuven, Ctr Canc Biol, VIB, B-3000 Leuven, Belgium; 2.Katholieke Univ Leuven, Dept Oncol, Herestr 49, B-3000 Leuven, Belgium; 3.Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Herestr 49, B-3000 Leuven, Belgium; 4.NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA; 5.Katholieke Univ Leuven, Dept Human Genet, Herestr 49, B-3000 Leuven, Belgium; 6.VIB Med Biotechnol Ctr, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium; 7.Univ Ghent, Dept Biochem, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium; 8.VIB Prote Core, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium; 9.Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA; 10.Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel; 11.Maastricht Univ, Fac Hlth Med & Life Sci, Dept Cardiol, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands; 12.Netherlands Heart Inst, NI HI, Utrecht, Netherlands
推荐引用方式 GB/T 7714	Steklov, M.,Pandolf, S.,Baietti, M. F.,et al. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination[J]. SCIENCE,2018,362(6419):1177-+.
APA	Steklov, M..,Pandolf, S..,Baietti, M. F..,Batiuk, A..,Carai, P..,...&Sablina, A. A..(2018).Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.SCIENCE,362(6419),1177-+.
MLA	Steklov, M.,et al."Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination".SCIENCE 362.6419(2018):1177-+.