NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways

Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB sub...

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Bibliographic Details
Published in:PLoS genetics 2020-06, Vol.16 (6), p.e1008863-e1008863
Main Authors: Sheng, Zhentao, Du, Wei
Format: Article
Language:English
Subjects:
Acetyltransferase
Apoptosis
Biology and Life Sciences
Cell adhesion & migration
Cell cycle
Cell death
Cell growth
Cell proliferation
Cell survival
Cellular signal transduction
Cloning
DNA damage
Drosophila
Epidermal growth factor receptors
Genetic aspects
Genetic regulation
Genetic screening
Grb2 protein
Insects
MAP kinase
Medical research
Medicine and Health Sciences
Metabolism
Mutants
Mutation
N-terminal acetyltransferase
Observations
Physiological aspects
Post-transcription
Research and Analysis Methods
Signal transduction
Therapeutic applications
Tumor suppressor genes
Ubiquitin
Ubiquitin-protein ligase
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Summary:Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. As inactivation of Psid blocked EGFR signaling-dependent tumor growth, this study raises the possibility that NatB is potentially a novel therapeutic target for cancers dependent on deregulated EGFR/Ras signaling.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1008863