Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function
Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic...
Gespeichert in:
Veröffentlicht in: | Molecular biology of the cell 2000-02, Vol.11 (2), p.735-746 |
---|---|
Hauptverfasser: | , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 746 |
---|---|
container_issue | 2 |
container_start_page | 735 |
container_title | Molecular biology of the cell |
container_volume | 11 |
creator | Ueno, H Kondo, E Yamamoto-Honda, R Tobe, K Nakamoto, T Sasaki, K Mitani, K Furusaka, A Tanaka, T Tsujimoto, Y Kadowaki, T Hirai, H |
description | Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2. |
doi_str_mv | 10.1091/mbc.11.2.735 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_14806</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>70940192</sourcerecordid><originalsourceid>FETCH-LOGICAL-c410t-f0b209fd782922aa356b1d1ec4f6c923153b5fe1c177004eac93e8114ca04dbe3</originalsourceid><addsrcrecordid>eNpVUU1v1DAQtRAVLQs3zsgnTs0y4zjJWuLSVnxJlXqBs-U4Y9YoawfbAfXYf45XW6FyGM1I782bN3qMvUHYIih8fxjtFnErtkPbPWMXqFrVyG7XP68zdKrBTshz9jLnnwAoZT-8YOcI_aBADBfs4SrnaL0pPgYeHfchr7MPPJGlpcTE8zrmkkwhvqRYqOL8jy97fm3nRnATJl725BMn58iWzKuMr23Zx1wr3c8n6SPRhOLNEqts8Za7Ndgj9IqdOTNnev3YN-z7p4_fbr40t3efv95c3TZWIpTGwShAuWnYCSWEMW3XjzghWel6q0SLXTt2jtDiMABIMla1tEOU1oCcRmo37MNJd1nHA02WQn1r1kvyB5PudTRe_48Ev9c_4m-Ncgd9XX_3uJ7ir5Vy0QefLc2zCRTXrAdQErAa2bDLE9GmmHMi9-8Egj4mpmtiGlELXROr9LdPbT0hnyJq_wJ-95a7</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>70940192</pqid></control><display><type>article</type><title>Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function</title><source>MEDLINE</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Ueno, H ; Kondo, E ; Yamamoto-Honda, R ; Tobe, K ; Nakamoto, T ; Sasaki, K ; Mitani, K ; Furusaka, A ; Tanaka, T ; Tsujimoto, Y ; Kadowaki, T ; Hirai, H</creator><contributor>Raff, Martin</contributor><creatorcontrib>Ueno, H ; Kondo, E ; Yamamoto-Honda, R ; Tobe, K ; Nakamoto, T ; Sasaki, K ; Mitani, K ; Furusaka, A ; Tanaka, T ; Tsujimoto, Y ; Kadowaki, T ; Hirai, H ; Raff, Martin</creatorcontrib><description>Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2.</description><identifier>ISSN: 1059-1524</identifier><identifier>EISSN: 1939-4586</identifier><identifier>DOI: 10.1091/mbc.11.2.735</identifier><identifier>PMID: 10679027</identifier><language>eng</language><publisher>United States: The American Society for Cell Biology</publisher><subject>Animals ; Apoptosis - drug effects ; Apoptosis Regulatory Proteins ; bcl-2-Associated X Protein ; bcl-X Protein ; Binding Sites ; Cell Line ; Humans ; Insulin - pharmacology ; Insulin Receptor Substrate Proteins ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Models, Biological ; Molecular Weight ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoproteins - antagonists & inhibitors ; Phosphoproteins - chemistry ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Phosphorylation - drug effects ; Phosphotyrosine - metabolism ; Protein Binding ; Protein Structure, Tertiary ; Proteins - genetics ; Proteins - metabolism ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2 - chemistry ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Signal Transduction - drug effects ; Transfection</subject><ispartof>Molecular biology of the cell, 2000-02, Vol.11 (2), p.735-746</ispartof><rights>Copyright © 2000, The American Society for Cell Biology 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-f0b209fd782922aa356b1d1ec4f6c923153b5fe1c177004eac93e8114ca04dbe3</citedby><cites>FETCH-LOGICAL-c410t-f0b209fd782922aa356b1d1ec4f6c923153b5fe1c177004eac93e8114ca04dbe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC14806/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC14806/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10679027$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Raff, Martin</contributor><creatorcontrib>Ueno, H</creatorcontrib><creatorcontrib>Kondo, E</creatorcontrib><creatorcontrib>Yamamoto-Honda, R</creatorcontrib><creatorcontrib>Tobe, K</creatorcontrib><creatorcontrib>Nakamoto, T</creatorcontrib><creatorcontrib>Sasaki, K</creatorcontrib><creatorcontrib>Mitani, K</creatorcontrib><creatorcontrib>Furusaka, A</creatorcontrib><creatorcontrib>Tanaka, T</creatorcontrib><creatorcontrib>Tsujimoto, Y</creatorcontrib><creatorcontrib>Kadowaki, T</creatorcontrib><creatorcontrib>Hirai, H</creatorcontrib><title>Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function</title><title>Molecular biology of the cell</title><addtitle>Mol Biol Cell</addtitle><description>Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis Regulatory Proteins</subject><subject>bcl-2-Associated X Protein</subject><subject>bcl-X Protein</subject><subject>Binding Sites</subject><subject>Cell Line</subject><subject>Humans</subject><subject>Insulin - pharmacology</subject><subject>Insulin Receptor Substrate Proteins</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Membrane Proteins</subject><subject>Models, Biological</subject><subject>Molecular Weight</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoproteins - antagonists & inhibitors</subject><subject>Phosphoproteins - chemistry</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Phosphotyrosine - metabolism</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins - genetics</subject><subject>Proteins - metabolism</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-bcl-2 - chemistry</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Transfection</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1v1DAQtRAVLQs3zsgnTs0y4zjJWuLSVnxJlXqBs-U4Y9YoawfbAfXYf45XW6FyGM1I782bN3qMvUHYIih8fxjtFnErtkPbPWMXqFrVyG7XP68zdKrBTshz9jLnnwAoZT-8YOcI_aBADBfs4SrnaL0pPgYeHfchr7MPPJGlpcTE8zrmkkwhvqRYqOL8jy97fm3nRnATJl725BMn58iWzKuMr23Zx1wr3c8n6SPRhOLNEqts8Za7Ndgj9IqdOTNnev3YN-z7p4_fbr40t3efv95c3TZWIpTGwShAuWnYCSWEMW3XjzghWel6q0SLXTt2jtDiMABIMla1tEOU1oCcRmo37MNJd1nHA02WQn1r1kvyB5PudTRe_48Ev9c_4m-Ncgd9XX_3uJ7ir5Vy0QefLc2zCRTXrAdQErAa2bDLE9GmmHMi9-8Egj4mpmtiGlELXROr9LdPbT0hnyJq_wJ-95a7</recordid><startdate>20000201</startdate><enddate>20000201</enddate><creator>Ueno, H</creator><creator>Kondo, E</creator><creator>Yamamoto-Honda, R</creator><creator>Tobe, K</creator><creator>Nakamoto, T</creator><creator>Sasaki, K</creator><creator>Mitani, K</creator><creator>Furusaka, A</creator><creator>Tanaka, T</creator><creator>Tsujimoto, Y</creator><creator>Kadowaki, T</creator><creator>Hirai, H</creator><general>The American Society for Cell Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20000201</creationdate><title>Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function</title><author>Ueno, H ; Kondo, E ; Yamamoto-Honda, R ; Tobe, K ; Nakamoto, T ; Sasaki, K ; Mitani, K ; Furusaka, A ; Tanaka, T ; Tsujimoto, Y ; Kadowaki, T ; Hirai, H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-f0b209fd782922aa356b1d1ec4f6c923153b5fe1c177004eac93e8114ca04dbe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis Regulatory Proteins</topic><topic>bcl-2-Associated X Protein</topic><topic>bcl-X Protein</topic><topic>Binding Sites</topic><topic>Cell Line</topic><topic>Humans</topic><topic>Insulin - pharmacology</topic><topic>Insulin Receptor Substrate Proteins</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Membrane Proteins</topic><topic>Models, Biological</topic><topic>Molecular Weight</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoproteins - antagonists & inhibitors</topic><topic>Phosphoproteins - chemistry</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation - drug effects</topic><topic>Phosphotyrosine - metabolism</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Proteins - genetics</topic><topic>Proteins - metabolism</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-bcl-2 - chemistry</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ueno, H</creatorcontrib><creatorcontrib>Kondo, E</creatorcontrib><creatorcontrib>Yamamoto-Honda, R</creatorcontrib><creatorcontrib>Tobe, K</creatorcontrib><creatorcontrib>Nakamoto, T</creatorcontrib><creatorcontrib>Sasaki, K</creatorcontrib><creatorcontrib>Mitani, K</creatorcontrib><creatorcontrib>Furusaka, A</creatorcontrib><creatorcontrib>Tanaka, T</creatorcontrib><creatorcontrib>Tsujimoto, Y</creatorcontrib><creatorcontrib>Kadowaki, T</creatorcontrib><creatorcontrib>Hirai, H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular biology of the cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ueno, H</au><au>Kondo, E</au><au>Yamamoto-Honda, R</au><au>Tobe, K</au><au>Nakamoto, T</au><au>Sasaki, K</au><au>Mitani, K</au><au>Furusaka, A</au><au>Tanaka, T</au><au>Tsujimoto, Y</au><au>Kadowaki, T</au><au>Hirai, H</au><au>Raff, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function</atitle><jtitle>Molecular biology of the cell</jtitle><addtitle>Mol Biol Cell</addtitle><date>2000-02-01</date><risdate>2000</risdate><volume>11</volume><issue>2</issue><spage>735</spage><epage>746</epage><pages>735-746</pages><issn>1059-1524</issn><eissn>1939-4586</eissn><abstract>Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2.</abstract><cop>United States</cop><pub>The American Society for Cell Biology</pub><pmid>10679027</pmid><doi>10.1091/mbc.11.2.735</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1059-1524 |
ispartof | Molecular biology of the cell, 2000-02, Vol.11 (2), p.735-746 |
issn | 1059-1524 1939-4586 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_14806 |
source | MEDLINE; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Animals Apoptosis - drug effects Apoptosis Regulatory Proteins bcl-2-Associated X Protein bcl-X Protein Binding Sites Cell Line Humans Insulin - pharmacology Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Membrane Proteins Models, Biological Molecular Weight Phosphatidylinositol 3-Kinases - metabolism Phosphoproteins - antagonists & inhibitors Phosphoproteins - chemistry Phosphoproteins - genetics Phosphoproteins - metabolism Phosphorylation - drug effects Phosphotyrosine - metabolism Protein Binding Protein Structure, Tertiary Proteins - genetics Proteins - metabolism Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - chemistry Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Signal Transduction - drug effects Transfection |
title | Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-26T07%3A37%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Association%20of%20insulin%20receptor%20substrate%20proteins%20with%20Bcl-2%20and%20their%20effects%20on%20its%20phosphorylation%20and%20antiapoptotic%20function&rft.jtitle=Molecular%20biology%20of%20the%20cell&rft.au=Ueno,%20H&rft.date=2000-02-01&rft.volume=11&rft.issue=2&rft.spage=735&rft.epage=746&rft.pages=735-746&rft.issn=1059-1524&rft.eissn=1939-4586&rft_id=info:doi/10.1091/mbc.11.2.735&rft_dat=%3Cproquest_pubme%3E70940192%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=70940192&rft_id=info:pmid/10679027&rfr_iscdi=true |