Loading…

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...

Full description

Saved in:
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:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593
cites cdi_FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593
container_end_page e1008863
container_issue 6
container_start_page e1008863
container_title PLoS genetics
container_volume 16
creator Sheng, Zhentao
Du, Wei
description 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.
doi_str_mv 10.1371/journal.pgen.1008863
format article
fullrecord <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_2424469105</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A632950136</galeid><doaj_id>oai_doaj_org_article_2b19fda3966b49a9858ba0d95e0b6a30</doaj_id><sourcerecordid>A632950136</sourcerecordid><originalsourceid>FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593</originalsourceid><addsrcrecordid>eNqVk99v0zAQxyMEYmPwHyBhCQnBQzs7jp3kBalM26gYHSo_Xq1LfElTJXGxnY3-9zi0oBXtAeSHs86f-94P66LoOaNTxlN2ujaD7aGdbmrsp4zSLJP8QXTMhOCTNKHJwzv3o-iJc2tKucjy9HF0xGMhcpaL4-hmAf4dsVgPLXh0ZFmQbvDQe1Ji2xKN4FcEek380BlLamtug6PYks7oMaTpa3J-ebE8_Tj79IG4pg4ljT6_smaoV8EiWUwwCNihRbIJcrewdU-jRxW0Dp_t7Un09eL8y9n7ydX15fxsdjUp05T7iWaSAxO6AiarlGuGFcoqRlZqFouMJhkHncVlIYSkoCUyEWtAqJKCMylyfhK92OluWuPUfmROxUmcJDJnVARiviO0gbXa2KYDu1UGGvXLYWytwPqmbFHFBcsrDTyXskhyyDORFUB1LpAWEjgNWm_32YaiQ11i7y20B6KHL32zUrW5USmPc5bwIPB6L2DN9wGdV13jxo-AHs0w1h0azPJYsIC-_Au9v7s9VUNooOkrE_KWo6iayZBUUMZloKb3UOFo7JrS9Fg1wX8Q8OYgIDAef_gaBufU_PPyP9jFv7PX3w7ZV3fYFULrV860g29M7w7BZAeW1jhnsfrzIYyqcZV-T06Nq6T2q8R_Au56Dg0</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2424469105</pqid></control><display><type>article</type><title>NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways</title><source>Open Access: PubMed Central</source><source>Publicly Available Content Database</source><creator>Sheng, Zhentao ; Du, Wei</creator><contributor>Perrimon, Norbert</contributor><creatorcontrib>Sheng, Zhentao ; Du, Wei ; Perrimon, Norbert</creatorcontrib><description>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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1008863</identifier><identifier>PMID: 32559195</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Acetyltransferase ; Apoptosis ; Biology and Life Sciences ; Cell adhesion &amp; 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</subject><ispartof>PLoS genetics, 2020-06, Vol.16 (6), p.e1008863-e1008863</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Sheng, Du. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Sheng, Du 2020 Sheng, Du</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593</citedby><cites>FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593</cites><orcidid>0000-0003-3962-370X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2424469105/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2424469105?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25752,27923,27924,37011,37012,44589,53790,53792,74897</link.rule.ids></links><search><contributor>Perrimon, Norbert</contributor><creatorcontrib>Sheng, Zhentao</creatorcontrib><creatorcontrib>Du, Wei</creatorcontrib><title>NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways</title><title>PLoS genetics</title><description>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.</description><subject>Acetyltransferase</subject><subject>Apoptosis</subject><subject>Biology and Life Sciences</subject><subject>Cell adhesion &amp; migration</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell survival</subject><subject>Cellular signal transduction</subject><subject>Cloning</subject><subject>DNA damage</subject><subject>Drosophila</subject><subject>Epidermal growth factor receptors</subject><subject>Genetic aspects</subject><subject>Genetic regulation</subject><subject>Genetic screening</subject><subject>Grb2 protein</subject><subject>Insects</subject><subject>MAP kinase</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mutants</subject><subject>Mutation</subject><subject>N-terminal acetyltransferase</subject><subject>Observations</subject><subject>Physiological aspects</subject><subject>Post-transcription</subject><subject>Research and Analysis Methods</subject><subject>Signal transduction</subject><subject>Therapeutic applications</subject><subject>Tumor suppressor genes</subject><subject>Ubiquitin</subject><subject>Ubiquitin-protein ligase</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqVk99v0zAQxyMEYmPwHyBhCQnBQzs7jp3kBalM26gYHSo_Xq1LfElTJXGxnY3-9zi0oBXtAeSHs86f-94P66LoOaNTxlN2ujaD7aGdbmrsp4zSLJP8QXTMhOCTNKHJwzv3o-iJc2tKucjy9HF0xGMhcpaL4-hmAf4dsVgPLXh0ZFmQbvDQe1Ji2xKN4FcEek380BlLamtug6PYks7oMaTpa3J-ebE8_Tj79IG4pg4ljT6_smaoV8EiWUwwCNihRbIJcrewdU-jRxW0Dp_t7Un09eL8y9n7ydX15fxsdjUp05T7iWaSAxO6AiarlGuGFcoqRlZqFouMJhkHncVlIYSkoCUyEWtAqJKCMylyfhK92OluWuPUfmROxUmcJDJnVARiviO0gbXa2KYDu1UGGvXLYWytwPqmbFHFBcsrDTyXskhyyDORFUB1LpAWEjgNWm_32YaiQ11i7y20B6KHL32zUrW5USmPc5bwIPB6L2DN9wGdV13jxo-AHs0w1h0azPJYsIC-_Au9v7s9VUNooOkrE_KWo6iayZBUUMZloKb3UOFo7JrS9Fg1wX8Q8OYgIDAef_gaBufU_PPyP9jFv7PX3w7ZV3fYFULrV860g29M7w7BZAeW1jhnsfrzIYyqcZV-T06Nq6T2q8R_Au56Dg0</recordid><startdate>20200619</startdate><enddate>20200619</enddate><creator>Sheng, Zhentao</creator><creator>Du, Wei</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-3962-370X</orcidid></search><sort><creationdate>20200619</creationdate><title>NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways</title><author>Sheng, Zhentao ; Du, Wei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetyltransferase</topic><topic>Apoptosis</topic><topic>Biology and Life Sciences</topic><topic>Cell adhesion &amp; migration</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell growth</topic><topic>Cell proliferation</topic><topic>Cell survival</topic><topic>Cellular signal transduction</topic><topic>Cloning</topic><topic>DNA damage</topic><topic>Drosophila</topic><topic>Epidermal growth factor receptors</topic><topic>Genetic aspects</topic><topic>Genetic regulation</topic><topic>Genetic screening</topic><topic>Grb2 protein</topic><topic>Insects</topic><topic>MAP kinase</topic><topic>Medical research</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Mutants</topic><topic>Mutation</topic><topic>N-terminal acetyltransferase</topic><topic>Observations</topic><topic>Physiological aspects</topic><topic>Post-transcription</topic><topic>Research and Analysis Methods</topic><topic>Signal transduction</topic><topic>Therapeutic applications</topic><topic>Tumor suppressor genes</topic><topic>Ubiquitin</topic><topic>Ubiquitin-protein ligase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sheng, Zhentao</creatorcontrib><creatorcontrib>Du, Wei</creatorcontrib><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sheng, Zhentao</au><au>Du, Wei</au><au>Perrimon, Norbert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways</atitle><jtitle>PLoS genetics</jtitle><date>2020-06-19</date><risdate>2020</risdate><volume>16</volume><issue>6</issue><spage>e1008863</spage><epage>e1008863</epage><pages>e1008863-e1008863</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><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.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>32559195</pmid><doi>10.1371/journal.pgen.1008863</doi><orcidid>https://orcid.org/0000-0003-3962-370X</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1553-7404
ispartof PLoS genetics, 2020-06, Vol.16 (6), p.e1008863-e1008863
issn 1553-7404
1553-7390
1553-7404
language eng
recordid cdi_plos_journals_2424469105
source Open Access: PubMed Central; Publicly Available Content Database
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
title NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-11T19%3A53%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=NatB%20regulates%20Rb%20mutant%20cell%20death%20and%20tumor%20growth%20by%20modulating%20EGFR/MAPK%20signaling%20through%20the%20N-end%20rule%20pathways&rft.jtitle=PLoS%20genetics&rft.au=Sheng,%20Zhentao&rft.date=2020-06-19&rft.volume=16&rft.issue=6&rft.spage=e1008863&rft.epage=e1008863&rft.pages=e1008863-e1008863&rft.issn=1553-7404&rft.eissn=1553-7404&rft_id=info:doi/10.1371/journal.pgen.1008863&rft_dat=%3Cgale_plos_%3EA632950136%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2424469105&rft_id=info:pmid/32559195&rft_galeid=A632950136&rfr_iscdi=true