Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

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Science  07 Dec 2018:
Vol. 362, Issue 6419, pp. 1177-1182
DOI: 10.1126/science.aap7607

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  • RE: Is LZTR1-mediated disease attributed to RAS ubiquitination at K170?
    • Chuan-Ming Xie, Professor, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
    • Other Contributors:
      • Leida Zhang, Professor, Southwest Hospital, Third Military Medical University (Army Medical University)


    We read with great interest the recent article by Steklov et al. (1). By assessing the role of LZTR1 in driving human disease, they found that LZTR1 weakly binds to endogenous panRAS and then ubiquitinates HRAS at K170. They point out that mutation in LZTR1 downregulates RAS ubiquitination, subsequent inactivation of ERK signaling, which is consistent with literature (2). Understanding the crosstalk of LZTR1 and RAS signaling regulating human disease is quite important. The data do support the potential for LZTR1 to contribute to this crosstalk.

    However, there are gaps in the data which preclude the authors from establishing a conclusive view or model. From a broad view, the notion that three RAS isoforms with consistent evolutionary conservation of K170 does not mean that K170 is required for LZTR1-meidated ubiquitination of all RAS isoforms. Previous studies demonstrated that Ras differs in localization and its ubiquitination displays isoform specificity. For example, Rabex-5 induces both HRas and NRas ubiquitination but not KRas, which results in endosomal retention, negatively regulates ERK activation (3). Given the role of LZTR1-mediated HRAS ubiquitination and downstream ERK signaling, what’s the relationship between LZTR1 and Rabex-5 in regulation of ERK signaling via RAS ubiquitination? Do they recognize the same domain of RAS? The interaction between purified LZTR1 and RAS isoforms as well as in vitro ubiquitination assay needs to be...

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    Competing Interests: None declared.