Abstract
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.
Highlights
Rb is a tumor suppressor often inactivation in cancers [1,2]
N-terminal acetyltransferase B (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
Our observation that Nt-acetylation by NatB coordinately regulates some of the highly conserved positive and negative components of the EGFR/MAPK pathway suggest that Nt-acetylation and N-end rule pathways can play important roles regulating important signaling pathways
Summary
Rb is a tumor suppressor often inactivation in cancers [1,2]. Rb binds to large numbers of interacting proteins including E2F transcription factors and chromatin regulators to modulate diverse cellular processes, including cell proliferation, cell cycle checkpoint and DNA damage repair, chromatin dynamics, apoptosis, cell differentiation, etc [3,4,5,6,7,8]. The consequences of Rb inactivation in different cell types can be different, ranging from increased cell proliferation, increased cell death, or altered cell differentiation depending on specific cell context. Inactivation of the fly Retinoblastoma (Rb) homolog Rbf in the developing eye discs lead to ectopic cell proliferation in posterior undifferentiated cells but increased cell death in cells just anterior to the morphogenetic furrow (MF), where the eye progenitor cells arrest in G1 and initiate photoreceptor differentiation [15,16,17]. The biological consequences of Rbf-inactivation are different in distinct cell types, suggesting that Drosophila developing eye is an excellent model system to dissect the cell context-dependent modulation of Rb-inactivation in vivo
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