TY - JOUR
T1 - LZTR1 is a regulator of RAS ubiquitination and signaling
AU - Bigenzahn, Johannes W.
AU - Collu, Giovanna M.
AU - Kartnig, Felix
AU - Pieraks, Melanie
AU - Vladimer, Gregory I.
AU - Heinz, Leonhard X.
AU - Sedlyarov, Vitaly
AU - Schischlik, Fiorella
AU - Fauster, Astrid
AU - Rebsamen, Manuele
AU - Parapatics, Katja
AU - Blomen, Vincent A.
AU - Müller, André C.
AU - Winter, Georg E.
AU - Kralovics, Robert
AU - Brummelkamp, Thijn R.
AU - Mlodzik, Marek
AU - Superti-Furga, Giulio
N1 - Publisher Copyright:
© 2018 American Association for the Advancement of Science. All Rights Reserved.
PY - 2018/12/7
Y1 - 2018/12/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056880719&partnerID=8YFLogxK
U2 - 10.1126/science.aap8210
DO - 10.1126/science.aap8210
M3 - Article
C2 - 30442766
AN - SCOPUS:85056880719
SN - 0036-8075
VL - 362
SP - 1171
EP - 1177
JO - Science
JF - Science
IS - 6419
ER -