Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species
Dysregulation in cellular redox systems results in accumulation of reactive oxygen species (ROS), which are causally associated with a number of disease conditions. Transforming growth factor β-activated kinase 1 (TAK1) is a signaling intermediate of innate immune signaling pathways and is criticall...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (9), p.3365-3370 |
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creator | Omori, Emily Inagaki, Maiko Mishina, Yuji Matsumoto, Kunihiro Ninomiya-Tsuji, Jun |
description | Dysregulation in cellular redox systems results in accumulation of reactive oxygen species (ROS), which are causally associated with a number of disease conditions. Transforming growth factor β-activated kinase 1 (TAK1) is a signaling intermediate of innate immune signaling pathways and is critically involved in the redox regulation in vivo. Ablation of TAK1 causes accumulation of ROS, resulting in epithelial cell death and inflammation. Here we determine the mechanism by which TAK1 kinase is activated in epithelial tissues. TAB1 and TAB2 are structurally unrelated TAK1 binding protein partners. TAB2 is known to mediate polyubiquitin chain-dependent TAK1 activation in innate immune signaling pathways, whereas the role of TAB1 is not defined. We found that epithelial-specific TAB1 and TAB2 double- but not TAB1 or TAB2 single-knockout mice phenocopied epithelial-specific TAK1 knockout mice. We demonstrate that phosphorylation-dependent basal activity of TAK1 is dependent on TAB1. Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues. These results demonstrate that epithelial TAK1 activity is regulated through two unique, TAB1-dependent basal and TAB2-mediated stimuli-dependent mechanisms. |
doi_str_mv | 10.1073/pnas.1116188109 |
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Transforming growth factor β-activated kinase 1 (TAK1) is a signaling intermediate of innate immune signaling pathways and is critically involved in the redox regulation in vivo. Ablation of TAK1 causes accumulation of ROS, resulting in epithelial cell death and inflammation. Here we determine the mechanism by which TAK1 kinase is activated in epithelial tissues. TAB1 and TAB2 are structurally unrelated TAK1 binding protein partners. TAB2 is known to mediate polyubiquitin chain-dependent TAK1 activation in innate immune signaling pathways, whereas the role of TAB1 is not defined. We found that epithelial-specific TAB1 and TAB2 double- but not TAB1 or TAB2 single-knockout mice phenocopied epithelial-specific TAK1 knockout mice. We demonstrate that phosphorylation-dependent basal activity of TAK1 is dependent on TAB1. Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues. 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Transforming growth factor β-activated kinase 1 (TAK1) is a signaling intermediate of innate immune signaling pathways and is critically involved in the redox regulation in vivo. Ablation of TAK1 causes accumulation of ROS, resulting in epithelial cell death and inflammation. Here we determine the mechanism by which TAK1 kinase is activated in epithelial tissues. TAB1 and TAB2 are structurally unrelated TAK1 binding protein partners. TAB2 is known to mediate polyubiquitin chain-dependent TAK1 activation in innate immune signaling pathways, whereas the role of TAB1 is not defined. We found that epithelial-specific TAB1 and TAB2 double- but not TAB1 or TAB2 single-knockout mice phenocopied epithelial-specific TAK1 knockout mice. We demonstrate that phosphorylation-dependent basal activity of TAK1 is dependent on TAB1. Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues. These results demonstrate that epithelial TAK1 activity is regulated through two unique, TAB1-dependent basal and TAB2-mediated stimuli-dependent mechanisms.</description><subject>Adaptor Proteins, Signal Transducing - deficiency</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>binding proteins</subject><subject>Biological Sciences</subject><subject>cell death</subject><subject>Enzyme Activation</subject><subject>Epidermis</subject><subject>Epidermis - enzymology</subject><subject>Epithelial cells</subject><subject>Epithelial Cells - enzymology</subject><subject>Inflammation</subject><subject>Intestinal mucosa</subject><subject>Intestinal Mucosa - enzymology</subject><subject>Intestines</subject><subject>Keratinocytes</subject><subject>Keratinocytes - enzymology</subject><subject>MAP Kinase Kinase Kinases - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Oxidation-Reduction</subject><subject>Oxidative Stress</subject><subject>Phenotype</subject><subject>Phosphatases</subject><subject>Phosphorylation</subject><subject>Protein Processing, Post-Translational</subject><subject>Proteins</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Signal Transduction</subject><subject>Skin</subject><subject>TAK1 protein</subject><subject>transforming growth factors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkstu1DAUhi0EokNhzQrwsizS-prEG6SqKhdRiQXt2vI4duKS2MH2tPRNeA4ehGfCYcpM2RxbPt_5z7F_A_ASo2OMGnoye5WOMcY1bluMxCOwKhFXNRPoMVghRJqqZYQdgGcpXSOEBG_RU3BACKVYILICP89nlwczOjXCHJVPNsTJ-R72MdzmAVqlc4jw96-qbNyNyqaD31zpaiCGR5enn_Fb6BLcJ_MQw6YfYL4N0PnOzKYEn-Fk9KC8S1OBfQej6TdjKUhl97fYwPDjrjceptloZ9Jz8MSqMZkX9-shuHp_fnn2sbr48uHT2elFpZlgubK1KhckpFbccN4xZjvKmVoz22pudGOpVhyXE8S1FWuClzfgXFi6VgY1DT0E77a682Y9mU6XWaMa5RzdpOKdDMrJ_zPeDbIPN5ISwQnHReDoXiCG7xuTspxc0mYclTdhk2Tp2LaU4bou6MkW1TGkFI3dtcFILn7KxU-597NUvH443Y7_Z-ADYKncywkpJKU1L8CrLXCdipE7gmGOasGXmd5s81YFqfrokrz6ShBm5bfUom0b-gfl_r2r</recordid><startdate>20120228</startdate><enddate>20120228</enddate><creator>Omori, Emily</creator><creator>Inagaki, Maiko</creator><creator>Mishina, Yuji</creator><creator>Matsumoto, Kunihiro</creator><creator>Ninomiya-Tsuji, Jun</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20120228</creationdate><title>Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species</title><author>Omori, Emily ; Inagaki, Maiko ; Mishina, Yuji ; Matsumoto, Kunihiro ; Ninomiya-Tsuji, Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c494t-f6a842226a5e55d44fd354ab4f8c5ec7f3ca5154a05cf9b210095559f3bae0773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adaptor Proteins, Signal Transducing - deficiency</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>binding proteins</topic><topic>Biological Sciences</topic><topic>cell death</topic><topic>Enzyme Activation</topic><topic>Epidermis</topic><topic>Epidermis - enzymology</topic><topic>Epithelial cells</topic><topic>Epithelial Cells - enzymology</topic><topic>Inflammation</topic><topic>Intestinal mucosa</topic><topic>Intestinal Mucosa - enzymology</topic><topic>Intestines</topic><topic>Keratinocytes</topic><topic>Keratinocytes - enzymology</topic><topic>MAP Kinase Kinase Kinases - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Oxidation-Reduction</topic><topic>Oxidative Stress</topic><topic>Phenotype</topic><topic>Phosphatases</topic><topic>Phosphorylation</topic><topic>Protein Processing, Post-Translational</topic><topic>Proteins</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Signal Transduction</topic><topic>Skin</topic><topic>TAK1 protein</topic><topic>transforming growth factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Omori, Emily</creatorcontrib><creatorcontrib>Inagaki, Maiko</creatorcontrib><creatorcontrib>Mishina, Yuji</creatorcontrib><creatorcontrib>Matsumoto, Kunihiro</creatorcontrib><creatorcontrib>Ninomiya-Tsuji, Jun</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Omori, Emily</au><au>Inagaki, Maiko</au><au>Mishina, Yuji</au><au>Matsumoto, Kunihiro</au><au>Ninomiya-Tsuji, Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2012-02-28</date><risdate>2012</risdate><volume>109</volume><issue>9</issue><spage>3365</spage><epage>3370</epage><pages>3365-3370</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Dysregulation in cellular redox systems results in accumulation of reactive oxygen species (ROS), which are causally associated with a number of disease conditions. Transforming growth factor β-activated kinase 1 (TAK1) is a signaling intermediate of innate immune signaling pathways and is critically involved in the redox regulation in vivo. Ablation of TAK1 causes accumulation of ROS, resulting in epithelial cell death and inflammation. Here we determine the mechanism by which TAK1 kinase is activated in epithelial tissues. TAB1 and TAB2 are structurally unrelated TAK1 binding protein partners. TAB2 is known to mediate polyubiquitin chain-dependent TAK1 activation in innate immune signaling pathways, whereas the role of TAB1 is not defined. We found that epithelial-specific TAB1 and TAB2 double- but not TAB1 or TAB2 single-knockout mice phenocopied epithelial-specific TAK1 knockout mice. We demonstrate that phosphorylation-dependent basal activity of TAK1 is dependent on TAB1. Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues. These results demonstrate that epithelial TAK1 activity is regulated through two unique, TAB1-dependent basal and TAB2-mediated stimuli-dependent mechanisms.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>22331902</pmid><doi>10.1073/pnas.1116188109</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adaptor Proteins, Signal Transducing - deficiency Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Apoptosis binding proteins Biological Sciences cell death Enzyme Activation Epidermis Epidermis - enzymology Epithelial cells Epithelial Cells - enzymology Inflammation Intestinal mucosa Intestinal Mucosa - enzymology Intestines Keratinocytes Keratinocytes - enzymology MAP Kinase Kinase Kinases - metabolism Mice Mice, Knockout Oxidation-Reduction Oxidative Stress Phenotype Phosphatases Phosphorylation Protein Processing, Post-Translational Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Signal Transduction Skin TAK1 protein transforming growth factors |
title | Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species |
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