Publikationsdatum:
2018
Beschreibung:
〈p〉The 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 〈i〉LZTR1〈/i〉 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.〈/p〉
Print ISSN:
0036-8075
Digitale ISSN:
1095-9203
Thema:
Allgemeine Naturwissenschaft
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