Who regulates the key regulator? The Superti-Furga laboratory at CeMM reports online in the journal Science about a newly discovered mechanism by which RAS proteins, central to cancer signaling, are regulated in their activity and localization.

Of the more than 23,000 genes in the human genome, only a handful assume a very central role in signal transduction and growth regulation. Of these, the three genes encoding RAS proteins are particularly important, as they are found mutated in over 25% of human cancers. The processes around the RAS gene products are also involved in a variety of rare human developmental disorders called the RASopathies. RAS proteins are absolutely central regulators of growth and oncogenesis and, in turn, every regulator of RAS is poised to be fundamentally important for cancer and a broad variety of human diseases.

Driven by the interest in identifying underlying genetic determinants of drug response in a specific type of cancer of the hematopoietic system, CeMM now reports on the mechanistic link between the LZTR1 gene, previously associated with a variety of rare disorders and rare cancers, and RAS. These findings provide a new key regulator of a pathway that is one of the best studied signaling pathways in biology. As such, it represents a major advancement. The study not only sheds new light and details on the regulation of a central growth-promoting protein, but also offers a molecular explanation for an unusually large number of pathological conditions, ranging from different types of brain and pediatric cancers to developmental pathologies like Noonan syndrome.

The research team found that the protein called LZTR1, in concert with its copartner cullin 3, regulates RAS by attaching to it a small molecular tag, called ubiquitin. The modified RAS proteins demonstrate altered localization within the cell and reduced abundance. Mutational defects or inactivation of LZTR1 lead to an increase of RAS dependent pathways causing dysregulation of growth and differentiation. LZTR1 can therefore be considered a breaker of RAS action.

Publication:
Johannes W. Bigenzahn, Giovanna M. Collu, Felix Kartnig, Melanie Pieraks, Gregory I. Vladimer, Leonhard X. Heinz, Vitaly Sedlyarov, Fiorella Schischlik, Astrid Fauster, Manuele Rebsamen, Katja Parapatics, Vincent A. Blomen, André C. Müller, Georg E. Winter, Robert Kralovics, Thijn R. Brummelkamp, Marek Mlodzik, Giulio Superti-Furga. LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018 November 15. doi:10.1126/science.aap8210.

Funding:
The study was supported by the following funding agencies and grants: Austrian Academy of Sciences, European Research Council (ERC) grants (i-FIVE 250179 and Game of Gates 695214) and starting grant (ERC-2012-StG 309634), Austrian Science Fund grant (FWF SFB F4711 and F4702), EMBO (ALTF 1346-2011, 1543-2012), NIH grants R01 EY013256 and GM102811, Cancer Genomics Center (CGC.nl), KWF grant NKI 2015-7609.