LZTR1 is a regulator of RAS ubiquitination and signaling

• Published in: Science (American Association for the Advancement of Science) Vol. 362; no. 6419; pp. 1171 - 1177
• Main Authors: Bigenzahn, Johannes W., Collu, Giovanna M., Kartnig, Felix, Pieraks, Melanie, Vladimer, Gregory I., Heinz, Leonhard X., Sedlyarov, Vitaly, Schischlik, Fiorella, Fauster, Astrid, Rebsamen, Manuele, Parapatics, Katja, Blomen, Vincent A., Müller, André C., Winter, Georg E., Kralovics, Robert, Brummelkamp, Thijn R., Mlodzik, Marek, Superti-Furga, Giulio
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 07.12.2018
• Subjects: Adapter proteins; Adapters; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; BCR-ABL protein; Cell Line, Tumor; Chronic myeloid leukemia; Cullin; Deactivation; Developmental disabilities; Drosophila melanogaster; Drug resistance; Drug Resistance, Neoplasm - genetics; Fruit flies; Fusion protein; Fusion Proteins, bcr-abl - antagonists & inhibitors; Gain of Function Mutation; Gene Knockdown Techniques; Genetic screening; Guanosine; Homology; Humans; Imidazoles - pharmacology; Imidazoles - therapeutic use; Inactivation; Inhibitors; Isoforms; Kinases; Leucine; Leucine zipper proteins; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - epidemiology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Localization; Loss of Function Mutation; MAP kinase; MAP Kinase Signaling System - genetics; Mutation; Myeloid leukemia; Noonan's syndrome; Phenotypes; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins p21(ras) - metabolism; Pyridazines - pharmacology; Pyridazines - therapeutic use; Sarcoma; Signal Transduction; Signaling; Transcription; Transcription Factors - genetics; Transcription Factors - physiology; Triphosphatase; Tyrosine; Ubiquitination; Ubiquitination - genetics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aap8210

The protein LZTR1 is mutated in human cancers and developmental diseases. Work from two groups now converges to implicate the protein in regulating signaling by the small guanosine triphosphatase RAS. Steklov et al. showed that mice haploinsufficient for LZTR1 recapitulated aspects of the human disease Noonan syndrome. Their biochemical studies showed that LZTR1 associated with RAS. LZTR1 appears to function as an adaptor that promotes ubiquitination of RAS, thus inhibiting its signaling functions. Bigenzahn et al. found LZTR1 in a screen for proteins whose absence led to resistance to the tyrosine kinase inhibitors used to treat cancers caused by the BCR-ABL oncogene product. Their biochemical studies and genetic studies in fruitflies also showed that loss of LZTR1 led to increased activity of RAS and signaling through the mitogen-activated protein kinase pathway. Science , this issue p. 1177 , p. 1171 Altered ubiquitination of RAS GTPases is implicated in cancer drug resistance. In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 ( LZTR1 ) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because LZTR1 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders.