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Loss-of-function of ubiquitin ligase adaptor LZTR1 triggers human disease by dysregulating RAS ubiquitination

ABSTRACT: Mutations in LZTR1, a substrate adaptor for cullin 3 (CUL3) ubiquitin ligase complexes1, have been recently associated with Noonan syndrome2,3 and familial Schwannomatosis4-6. Concordantly, we found that Lztr1+/- mice showed craniofacial abnormalities, cardio defects, and premature ageing; whereas loss of LZTR1 in Schwann cells drives their dedifferentiation into proliferating, pro-myelinating cells. We screened for LZTR1 substrates by trapping LZTR1 complexes from intact mammalian cells. In parallel, we analysed changes in the ubiquitin landscape induced by LZTR1 loss of function. RAS proteins emerged as substrates of the LZTR1/CUL3 complex, which inhibits the RAS pathway by ubiquitinating RAS at K170 and triggering its dissociation from the membrane. Disease-associated LZTR1 mutations affect either the LZTR1/CUL3 complex formation, or the interaction with RAS proteins. These results position LZTR1 as a key node in the RAS pathway, loss-of-function of which leads to a human disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Sven Eyckerman

LAB HEAD: Sven Eyckerman

PROVIDER: PXD007049 | Pride | 2018-11-04

REPOSITORIES: Pride

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			Action	DRS
	HRASeDHFRcontrol1.raw	Raw
	HRASeDHFRcontrol2.raw	Raw
	HRASeDHFRcontrol3.raw	Raw
	HRASrepeat1.raw	Raw
	HRASrepeat2.raw	Raw

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Phosphorylation of the multi functional signal transducer B-cell adaptor protein (BCAP) facilitates recruitment of multiple SH2/SH3 proteins including Grb2.

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Loss-of-function of ubiquitin ligase adaptor LZTR1 triggers human disease by dysregulating RAS ubiquitination

Project description:Mutations in LZTR1, a substrate adaptor for cullin 3 (CUL3) ubiquitin ligase complexes, have been recently associated with Noonan syndrome and familial Schwannomatosis. Concordantly, we found that Lztr1+/- mice showed craniofacial abnormalities, cardio defects, and premature ageing; whereas loss of LZTR1 in Schwann cells drives their dedifferentiation into proliferating, pro-myelinating cells. In the present dataset we screened for changes in the ubiquitin landscape induced by LZTR1 loss of function by mass spectrometry-based proteomics and identified RAS proteins as substrates of the LZTR1/CUL3 complex. In follow-up experiments we showed that LZTR1/CUL3 inhibits the RAS pathway by ubiquitinating RAS at K170 and triggering its dissociation from the membrane. Disease-associated LZTR1 mutations affect either the LZTR1/CUL3 complex formation, or the interaction with RAS proteins. Together, our results position LZTR1 as a key node in the RAS pathway, loss-of-function of which leads to human disease.

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