The SH2 domain and kinase activity of JAK2 target JAK2 to centrosome and regulate cell growth and centrosome amplification
JAK2 is cytokine-activated non-receptor tyrosine kinase. Although JAK2 is mainly localized at the plasma membrane, it is also present on the centrosome. In this study, we demonstrated that JAK2 localization to the centrosome depends on the SH2 domain and intact kinase activity. We created JAK2 mutan...
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| description | JAK2 is cytokine-activated non-receptor tyrosine kinase. Although JAK2 is mainly localized at the plasma membrane, it is also present on the centrosome. In this study, we demonstrated that JAK2 localization to the centrosome depends on the SH2 domain and intact kinase activity. We created JAK2 mutants deficient in centrosomal localization ΔSH2, K882E and (ΔSH2, K882E). We showed that JAK2 WT clone strongly enhances cell proliferation as compared to control cells while JAK2 clones ΔSH2, K882E and (ΔSH2, K882E) proliferate slower than JAK2 WT cells. These mutant clones also progress much slower through the cell cycle as compared to JAK2 WT clone and the enhanced proliferation of JAK2 WT cells is accompanied by increased S -> G2 progression. Both the SH2 domain and the kinase activity of JAK2 play a role in prolactin-dependent activation of JAK2 substrate STAT5. We showed that JAK2 is an important regulator of centrosome function as the SH2 domain of JAK2 regulates centrosome amplification. The cells overexpressing ΔSH2 and (ΔSH2, K-E) JAK2 have almost three-fold the amplified centrosomes of WT cells. In contrast, the kinase activity of JAK2 is dispensable for centrosome amplification. Our observations provide novel insight into the role of SH2 domain and kinase activity of JAK2 in centrosome localization of JAK2 and in the regulation of cell growth and centrosome biogenesis. |
| doi_str_mv | 10.1371/journal.pone.0261098 |
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Although JAK2 is mainly localized at the plasma membrane, it is also present on the centrosome. In this study, we demonstrated that JAK2 localization to the centrosome depends on the SH2 domain and intact kinase activity. We created JAK2 mutants deficient in centrosomal localization ΔSH2, K882E and (ΔSH2, K882E). We showed that JAK2 WT clone strongly enhances cell proliferation as compared to control cells while JAK2 clones ΔSH2, K882E and (ΔSH2, K882E) proliferate slower than JAK2 WT cells. These mutant clones also progress much slower through the cell cycle as compared to JAK2 WT clone and the enhanced proliferation of JAK2 WT cells is accompanied by increased S -> G2 progression. Both the SH2 domain and the kinase activity of JAK2 play a role in prolactin-dependent activation of JAK2 substrate STAT5. We showed that JAK2 is an important regulator of centrosome function as the SH2 domain of JAK2 regulates centrosome amplification. The cells overexpressing ΔSH2 and (ΔSH2, K-E) JAK2 have almost three-fold the amplified centrosomes of WT cells. In contrast, the kinase activity of JAK2 is dispensable for centrosome amplification. Our observations provide novel insight into the role of SH2 domain and kinase activity of JAK2 in centrosome localization of JAK2 and in the regulation of cell growth and centrosome biogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0261098</identifier><identifier>PMID: 35089929</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alzheimer's disease ; Amplification ; Animals ; Biology and Life Sciences ; Cell cycle ; Cell Cycle Checkpoints ; Cell division ; Cell growth ; Cell Line ; Cell Proliferation ; Cellular control mechanisms ; Centrosome - metabolism ; Centrosomes ; Chlorocebus aethiops ; Chromosomes ; Cloning ; COS Cells ; Cytokines ; Domains ; Engineering and Technology ; Gene amplification ; Gene expression ; Genetic aspects ; Health aspects ; Humans ; Interferon-gamma - pharmacology ; Janus kinase 2 ; Janus Kinase 2 - chemistry ; Janus Kinase 2 - genetics ; Janus Kinase 2 - metabolism ; Kinases ; Localization ; Mutagenesis, Site-Directed ; Mutants ; Mutation ; Phosphotransferases ; Prolactin ; Protein Transport - drug effects ; Protein-tyrosine kinase receptors ; Proteins ; Research and Analysis Methods ; Signal transduction ; src Homology Domains - genetics ; Stat5 protein ; STAT5 Transcription Factor - metabolism ; Substrates ; Tyrosine</subject><ispartof>PloS one, 2022-01, Vol.17 (1), p.e0261098-e0261098</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Shahi et al. 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. 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Although JAK2 is mainly localized at the plasma membrane, it is also present on the centrosome. In this study, we demonstrated that JAK2 localization to the centrosome depends on the SH2 domain and intact kinase activity. We created JAK2 mutants deficient in centrosomal localization ΔSH2, K882E and (ΔSH2, K882E). We showed that JAK2 WT clone strongly enhances cell proliferation as compared to control cells while JAK2 clones ΔSH2, K882E and (ΔSH2, K882E) proliferate slower than JAK2 WT cells. These mutant clones also progress much slower through the cell cycle as compared to JAK2 WT clone and the enhanced proliferation of JAK2 WT cells is accompanied by increased S -> G2 progression. Both the SH2 domain and the kinase activity of JAK2 play a role in prolactin-dependent activation of JAK2 substrate STAT5. We showed that JAK2 is an important regulator of centrosome function as the SH2 domain of JAK2 regulates centrosome amplification. The cells overexpressing ΔSH2 and (ΔSH2, K-E) JAK2 have almost three-fold the amplified centrosomes of WT cells. In contrast, the kinase activity of JAK2 is dispensable for centrosome amplification. Our observations provide novel insight into the role of SH2 domain and kinase activity of JAK2 in centrosome localization of JAK2 and in the regulation of cell growth and centrosome biogenesis.</description><subject>Alzheimer's disease</subject><subject>Amplification</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Cell cycle</subject><subject>Cell Cycle Checkpoints</subject><subject>Cell division</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Cellular control mechanisms</subject><subject>Centrosome - metabolism</subject><subject>Centrosomes</subject><subject>Chlorocebus aethiops</subject><subject>Chromosomes</subject><subject>Cloning</subject><subject>COS Cells</subject><subject>Cytokines</subject><subject>Domains</subject><subject>Engineering and Technology</subject><subject>Gene amplification</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Interferon-gamma - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shahi, Aashirwad</au><au>Kahle, Jacob</au><au>Hopkins, Chandler</au><au>Diakonova, Maria</au><au>Buday, Laszlo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The SH2 domain and kinase activity of JAK2 target JAK2 to centrosome and regulate cell growth and centrosome amplification</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2022-01-28</date><risdate>2022</risdate><volume>17</volume><issue>1</issue><spage>e0261098</spage><epage>e0261098</epage><pages>e0261098-e0261098</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>JAK2 is cytokine-activated non-receptor tyrosine kinase. Although JAK2 is mainly localized at the plasma membrane, it is also present on the centrosome. In this study, we demonstrated that JAK2 localization to the centrosome depends on the SH2 domain and intact kinase activity. We created JAK2 mutants deficient in centrosomal localization ΔSH2, K882E and (ΔSH2, K882E). We showed that JAK2 WT clone strongly enhances cell proliferation as compared to control cells while JAK2 clones ΔSH2, K882E and (ΔSH2, K882E) proliferate slower than JAK2 WT cells. These mutant clones also progress much slower through the cell cycle as compared to JAK2 WT clone and the enhanced proliferation of JAK2 WT cells is accompanied by increased S -> G2 progression. Both the SH2 domain and the kinase activity of JAK2 play a role in prolactin-dependent activation of JAK2 substrate STAT5. We showed that JAK2 is an important regulator of centrosome function as the SH2 domain of JAK2 regulates centrosome amplification. The cells overexpressing ΔSH2 and (ΔSH2, K-E) JAK2 have almost three-fold the amplified centrosomes of WT cells. In contrast, the kinase activity of JAK2 is dispensable for centrosome amplification. Our observations provide novel insight into the role of SH2 domain and kinase activity of JAK2 in centrosome localization of JAK2 and in the regulation of cell growth and centrosome biogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>35089929</pmid><doi>10.1371/journal.pone.0261098</doi><tpages>e0261098</tpages><orcidid>https://orcid.org/0000-0002-4554-2730</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alzheimer's disease Amplification Animals Biology and Life Sciences Cell cycle Cell Cycle Checkpoints Cell division Cell growth Cell Line Cell Proliferation Cellular control mechanisms Centrosome - metabolism Centrosomes Chlorocebus aethiops Chromosomes Cloning COS Cells Cytokines Domains Engineering and Technology Gene amplification Gene expression Genetic aspects Health aspects Humans Interferon-gamma - pharmacology Janus kinase 2 Janus Kinase 2 - chemistry Janus Kinase 2 - genetics Janus Kinase 2 - metabolism Kinases Localization Mutagenesis, Site-Directed Mutants Mutation Phosphotransferases Prolactin Protein Transport - drug effects Protein-tyrosine kinase receptors Proteins Research and Analysis Methods Signal transduction src Homology Domains - genetics Stat5 protein STAT5 Transcription Factor - metabolism Substrates Tyrosine |
| title | The SH2 domain and kinase activity of JAK2 target JAK2 to centrosome and regulate cell growth and centrosome amplification |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T16%3A12%3A07IST&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=The%20SH2%20domain%20and%20kinase%20activity%20of%20JAK2%20target%20JAK2%20to%20centrosome%20and%20regulate%20cell%20growth%20and%20centrosome%20amplification&rft.jtitle=PloS%20one&rft.au=Shahi,%20Aashirwad&rft.date=2022-01-28&rft.volume=17&rft.issue=1&rft.spage=e0261098&rft.epage=e0261098&rft.pages=e0261098-e0261098&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0261098&rft_dat=%3Cgale_plos_%3EA690820969%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2623591415&rft_id=info:pmid/35089929&rft_galeid=A690820969&rft_doaj_id=oai_doaj_org_article_d9ea13386c514a549b0098c3b403968c&rfr_iscdi=true |