CD45 recruits adapter protein DOK-1 and negatively regulates JAK–STAT signaling in hematopoietic cells
It has been extensively documented that CD45 positively regulates T cell receptor-mediated signaling through the activation of Src-family kinases. The mechanism whereby CD45 negatively regulates the JAK/STAT pathway, however, has not been fully elucidated. Here we describe the mechanism by which CD4...
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Veröffentlicht in: | Molecular immunology 2009-07, Vol.46 (11), p.2167-2177 |
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description | It has been extensively documented that CD45 positively regulates T cell receptor-mediated signaling through the activation of Src-family kinases. The mechanism whereby CD45 negatively regulates the JAK/STAT pathway, however, has not been fully elucidated. Here we describe the mechanism by which CD45 negatively regulates the JAK/STAT pathway through the recruitment of the inhibitory molecule Downstream of Kinase 1 (DOK-1) in hematopoietic cells. We present evidences that CD45 recruits DOK-1 to associate with tyrosine-phosphorylated DOK-1, and that the DOK-1-Y296F mutant completely abrogates its interaction with CD45. Moreover, CD45 expression is required for DOK-1 targeting to the plasma membrane in response to anti-CD3 stimulation. Functional studies further showed that stable expression of DOK-1 in K562 cells markedly decreased both JAK-2 and STAT-3/5 phosphorylation following IL-3 and IFN-α stimulation. Likewise, stable expression of DOK-1 in Jurkat cells significantly decreased JAK-2 phosphorylation. Similarly, both IL-3 and IFN-α-induced JAK-2 phosphorylations were significantly increased in CD45 deficient Jurkat cells. Consistently, silencing of the DOK-1 gene resulted in rescue of MAP kinases and JAKs activities in CD45 positive Jurkat cells. Accordingly, CD45 recruits adaptor DOK-1 to the proximal plasma membrane to serve as a downstream effector, resulting in negative regulation of the JAK/STAT signaling pathway. |
doi_str_mv | 10.1016/j.molimm.2009.04.032 |
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The mechanism whereby CD45 negatively regulates the JAK/STAT pathway, however, has not been fully elucidated. Here we describe the mechanism by which CD45 negatively regulates the JAK/STAT pathway through the recruitment of the inhibitory molecule Downstream of Kinase 1 (DOK-1) in hematopoietic cells. We present evidences that CD45 recruits DOK-1 to associate with tyrosine-phosphorylated DOK-1, and that the DOK-1-Y296F mutant completely abrogates its interaction with CD45. Moreover, CD45 expression is required for DOK-1 targeting to the plasma membrane in response to anti-CD3 stimulation. Functional studies further showed that stable expression of DOK-1 in K562 cells markedly decreased both JAK-2 and STAT-3/5 phosphorylation following IL-3 and IFN-α stimulation. Likewise, stable expression of DOK-1 in Jurkat cells significantly decreased JAK-2 phosphorylation. Similarly, both IL-3 and IFN-α-induced JAK-2 phosphorylations were significantly increased in CD45 deficient Jurkat cells. Consistently, silencing of the DOK-1 gene resulted in rescue of MAP kinases and JAKs activities in CD45 positive Jurkat cells. Accordingly, CD45 recruits adaptor DOK-1 to the proximal plasma membrane to serve as a downstream effector, resulting in negative regulation of the JAK/STAT signaling pathway.</description><identifier>ISSN: 0161-5890</identifier><identifier>EISSN: 1872-9142</identifier><identifier>DOI: 10.1016/j.molimm.2009.04.032</identifier><identifier>PMID: 19481264</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>CD45 ; Cell Membrane - metabolism ; DNA-Binding Proteins - metabolism ; DOK-1 ; Humans ; Interferon-alpha - metabolism ; Interferon-alpha - pharmacology ; Interleukin-3 - metabolism ; Interleukin-3 - pharmacology ; JAKs ; Janus Kinase 2 - metabolism ; Jurkat Cells ; K562 Cells ; Leukocyte Common Antigens - genetics ; Leukocyte Common Antigens - physiology ; MAP Kinase Signaling System - physiology ; Mutation ; Negative regulation ; Phosphoproteins - metabolism ; Phosphorylation ; Protein Binding ; RNA-Binding Proteins - metabolism ; Signal Transduction ; STAT3 Transcription Factor - metabolism ; STAT5 Transcription Factor - metabolism ; STATs ; T-cells ; T-Lymphocytes - metabolism</subject><ispartof>Molecular immunology, 2009-07, Vol.46 (11), p.2167-2177</ispartof><rights>2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c457t-3465d80d99cb1b8b374111d7d71ab2fd76a55dfa2036788e0585412cd1dbe60a3</citedby><cites>FETCH-LOGICAL-c457t-3465d80d99cb1b8b374111d7d71ab2fd76a55dfa2036788e0585412cd1dbe60a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molimm.2009.04.032$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19481264$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Liangtang</creatorcontrib><creatorcontrib>Bijian, Krikor</creatorcontrib><creatorcontrib>Shen, Shi-Shiang</creatorcontrib><title>CD45 recruits adapter protein DOK-1 and negatively regulates JAK–STAT signaling in hematopoietic cells</title><title>Molecular immunology</title><addtitle>Mol Immunol</addtitle><description>It has been extensively documented that CD45 positively regulates T cell receptor-mediated signaling through the activation of Src-family kinases. The mechanism whereby CD45 negatively regulates the JAK/STAT pathway, however, has not been fully elucidated. Here we describe the mechanism by which CD45 negatively regulates the JAK/STAT pathway through the recruitment of the inhibitory molecule Downstream of Kinase 1 (DOK-1) in hematopoietic cells. We present evidences that CD45 recruits DOK-1 to associate with tyrosine-phosphorylated DOK-1, and that the DOK-1-Y296F mutant completely abrogates its interaction with CD45. Moreover, CD45 expression is required for DOK-1 targeting to the plasma membrane in response to anti-CD3 stimulation. Functional studies further showed that stable expression of DOK-1 in K562 cells markedly decreased both JAK-2 and STAT-3/5 phosphorylation following IL-3 and IFN-α stimulation. Likewise, stable expression of DOK-1 in Jurkat cells significantly decreased JAK-2 phosphorylation. Similarly, both IL-3 and IFN-α-induced JAK-2 phosphorylations were significantly increased in CD45 deficient Jurkat cells. Consistently, silencing of the DOK-1 gene resulted in rescue of MAP kinases and JAKs activities in CD45 positive Jurkat cells. Accordingly, CD45 recruits adaptor DOK-1 to the proximal plasma membrane to serve as a downstream effector, resulting in negative regulation of the JAK/STAT signaling pathway.</description><subject>CD45</subject><subject>Cell Membrane - metabolism</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>DOK-1</subject><subject>Humans</subject><subject>Interferon-alpha - metabolism</subject><subject>Interferon-alpha - pharmacology</subject><subject>Interleukin-3 - metabolism</subject><subject>Interleukin-3 - pharmacology</subject><subject>JAKs</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Jurkat Cells</subject><subject>K562 Cells</subject><subject>Leukocyte Common Antigens - genetics</subject><subject>Leukocyte Common Antigens - physiology</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mutation</subject><subject>Negative regulation</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>STAT5 Transcription Factor - metabolism</subject><subject>STATs</subject><subject>T-cells</subject><subject>T-Lymphocytes - metabolism</subject><issn>0161-5890</issn><issn>1872-9142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEUhS0EomnLGyDkFbsZbI__ZoMUpUChlbogXVse-yZ1ND_B9lTqjnfgDfskOEokdmV1N985995zEHpPSU0JlZ929TD1YRhqRkhbE16Thr1CC6oVq1rK2Wu0KBithG7JGTpPaUcIkUSKt-iMtlxTJvkCPayuuMARXJxDTth6u88Q8T5OGcKIr-5uKort6PEIW5vDI_RPhd7Ovc2Q8I_lzfPvPz_XyzVOYTvaPoxbXGQPMNg87acAOTjsoO_TJXqzsX2Cd6d5ge6_flmvrqvbu2_fV8vbynGhctVwKbwmvm1dRzvdNYpTSr3yitqObbySVgi_sYw0UmkNRGjBKXOe-g4ksc0F-nj0LS_8miFlM4R0uMCOMM3JSNVIqXXzX7DEqgRnrID8CLo4pRRhY_YxDDY-GUrMoQqzM8cqDprWEG5KFUX24eQ_dwP4f6JT9gX4fASgxPEYIJrkAowOfCh9ZOOn8PKGv6XDnHc</recordid><startdate>20090701</startdate><enddate>20090701</enddate><creator>Wu, Liangtang</creator><creator>Bijian, Krikor</creator><creator>Shen, Shi-Shiang</creator><general>Elsevier Ltd</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20090701</creationdate><title>CD45 recruits adapter protein DOK-1 and negatively regulates JAK–STAT signaling in hematopoietic cells</title><author>Wu, Liangtang ; Bijian, Krikor ; Shen, Shi-Shiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-3465d80d99cb1b8b374111d7d71ab2fd76a55dfa2036788e0585412cd1dbe60a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>CD45</topic><topic>Cell Membrane - metabolism</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>DOK-1</topic><topic>Humans</topic><topic>Interferon-alpha - metabolism</topic><topic>Interferon-alpha - pharmacology</topic><topic>Interleukin-3 - metabolism</topic><topic>Interleukin-3 - pharmacology</topic><topic>JAKs</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Jurkat Cells</topic><topic>K562 Cells</topic><topic>Leukocyte Common Antigens - genetics</topic><topic>Leukocyte Common Antigens - physiology</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mutation</topic><topic>Negative regulation</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>STAT5 Transcription Factor - metabolism</topic><topic>STATs</topic><topic>T-cells</topic><topic>T-Lymphocytes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Liangtang</creatorcontrib><creatorcontrib>Bijian, Krikor</creatorcontrib><creatorcontrib>Shen, Shi-Shiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Liangtang</au><au>Bijian, Krikor</au><au>Shen, Shi-Shiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD45 recruits adapter protein DOK-1 and negatively regulates JAK–STAT signaling in hematopoietic cells</atitle><jtitle>Molecular immunology</jtitle><addtitle>Mol Immunol</addtitle><date>2009-07-01</date><risdate>2009</risdate><volume>46</volume><issue>11</issue><spage>2167</spage><epage>2177</epage><pages>2167-2177</pages><issn>0161-5890</issn><eissn>1872-9142</eissn><abstract>It has been extensively documented that CD45 positively regulates T cell receptor-mediated signaling through the activation of Src-family kinases. The mechanism whereby CD45 negatively regulates the JAK/STAT pathway, however, has not been fully elucidated. Here we describe the mechanism by which CD45 negatively regulates the JAK/STAT pathway through the recruitment of the inhibitory molecule Downstream of Kinase 1 (DOK-1) in hematopoietic cells. We present evidences that CD45 recruits DOK-1 to associate with tyrosine-phosphorylated DOK-1, and that the DOK-1-Y296F mutant completely abrogates its interaction with CD45. Moreover, CD45 expression is required for DOK-1 targeting to the plasma membrane in response to anti-CD3 stimulation. Functional studies further showed that stable expression of DOK-1 in K562 cells markedly decreased both JAK-2 and STAT-3/5 phosphorylation following IL-3 and IFN-α stimulation. Likewise, stable expression of DOK-1 in Jurkat cells significantly decreased JAK-2 phosphorylation. Similarly, both IL-3 and IFN-α-induced JAK-2 phosphorylations were significantly increased in CD45 deficient Jurkat cells. Consistently, silencing of the DOK-1 gene resulted in rescue of MAP kinases and JAKs activities in CD45 positive Jurkat cells. Accordingly, CD45 recruits adaptor DOK-1 to the proximal plasma membrane to serve as a downstream effector, resulting in negative regulation of the JAK/STAT signaling pathway.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>19481264</pmid><doi>10.1016/j.molimm.2009.04.032</doi><tpages>11</tpages></addata></record> |
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subjects | CD45 Cell Membrane - metabolism DNA-Binding Proteins - metabolism DOK-1 Humans Interferon-alpha - metabolism Interferon-alpha - pharmacology Interleukin-3 - metabolism Interleukin-3 - pharmacology JAKs Janus Kinase 2 - metabolism Jurkat Cells K562 Cells Leukocyte Common Antigens - genetics Leukocyte Common Antigens - physiology MAP Kinase Signaling System - physiology Mutation Negative regulation Phosphoproteins - metabolism Phosphorylation Protein Binding RNA-Binding Proteins - metabolism Signal Transduction STAT3 Transcription Factor - metabolism STAT5 Transcription Factor - metabolism STATs T-cells T-Lymphocytes - metabolism |
title | CD45 recruits adapter protein DOK-1 and negatively regulates JAK–STAT signaling in hematopoietic cells |
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