Bigenzahn, J.W., Collu, G.M., Kartnig, F., Pieraks, M., Vladimer, G.I., Heinz, L.X., Sedlyarov, V., Schischlik, F., Fauster, A., Rebsamen, M., Parapatics, K., Blomen, V.A., Müller, A.C., Winter, G.E., Kralovics, R., Brummelkamp, T.R., Mlodzik, M., Superti-Furga, G. (2018). LZTR1 is a regulator of RAS ubiquitination and signaling.  Science 362(6419): 1171--1177.

FBrf0240886

Research paper

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.

PMC6794158 (PMC) (EuropePMC)