EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal
The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high EVI1 expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out...
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| creator | Paredes, Roberto Kelly, James R. Geary, Bethany Almarzouq, Batool Schneider, Marion Pearson, Stella Narayanan, Prakrithi Williamson, Andrew Lovell, Simon C. Wiseman, Daniel H. Chadwick, John A. Jones, Nigel J. Kustikova, Olga Schambach, Axel Garner, Terence Amaral, Fabio M. R. Pierce, Andrew Stevens, Adam Somervaille, Tim C. P. Whetton, Anthony D. Meyer, Stefan |
| description | The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high
EVI1
expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). Wild-type EVI1 (EVI1-WT) with S436 available for phosphorylation, but not non-phosphorylatable EVI1-S436A, conferred haematopoietic progenitor cell self-renewal and was associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed reduced affinity to CtBP1, and CtBP1 showed reduced interaction with EVI1-WT compared with EVI1-S436A. The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. These data point to EVI1-S436 phosphorylation directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may be of therapeutic benefit when treating EVI1-driven leukaemia. |
| doi_str_mv | 10.1038/s41419-020-03099-0 |
| format | Article |
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EVI1
expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). Wild-type EVI1 (EVI1-WT) with S436 available for phosphorylation, but not non-phosphorylatable EVI1-S436A, conferred haematopoietic progenitor cell self-renewal and was associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed reduced affinity to CtBP1, and CtBP1 showed reduced interaction with EVI1-WT compared with EVI1-S436A. The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. These data point to EVI1-S436 phosphorylation directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may be of therapeutic benefit when treating EVI1-driven leukaemia.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-020-03099-0</identifier><identifier>PMID: 33082307</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/58 ; 13/1 ; 13/31 ; 14/1 ; 14/10 ; 38/1 ; 38/77 ; 38/91 ; 45/91 ; 631/67/1990/283/1897 ; 64/60 ; 692/699/67/1990/283 ; 82/1 ; 82/58 ; 96/106 ; 96/31 ; Acute myeloid leukemia ; Alcohol Oxidoreductases - metabolism ; Antibodies ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Culture ; Cell Self Renewal - physiology ; Cell self-renewal ; Cyclin-dependent kinase 2 ; DNA (Cytosine-5-)-Methyltransferases - metabolism ; DNA Methylation - physiology ; DNA Methyltransferase 3A ; DNA Modification Methylases - metabolism ; DNA-Binding Proteins - metabolism ; Humans ; Immunology ; Leukemia ; Leukemia, Myeloid, Acute - metabolism ; Life Sciences ; Mass spectroscopy ; MDS1 and EVI1 Complex Locus Protein - metabolism ; Methyltransferase ; Phosphorylation ; Post-translation ; Progenitor cells ; Prognosis ; Protein interaction ; Serine ; Serine - metabolism ; Transcription ; Transcription Factors - metabolism</subject><ispartof>Cell death & disease, 2020-10, Vol.11 (10), p.878-878, Article 878</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. 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R.</creatorcontrib><creatorcontrib>Pierce, Andrew</creatorcontrib><creatorcontrib>Stevens, Adam</creatorcontrib><creatorcontrib>Somervaille, Tim C. P.</creatorcontrib><creatorcontrib>Whetton, Anthony D.</creatorcontrib><creatorcontrib>Meyer, Stefan</creatorcontrib><title>EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high
EVI1
expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). Wild-type EVI1 (EVI1-WT) with S436 available for phosphorylation, but not non-phosphorylatable EVI1-S436A, conferred haematopoietic progenitor cell self-renewal and was associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed reduced affinity to CtBP1, and CtBP1 showed reduced interaction with EVI1-WT compared with EVI1-S436A. The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. These data point to EVI1-S436 phosphorylation directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may be of therapeutic benefit when treating EVI1-driven leukaemia.</description><subject>101/58</subject><subject>13/1</subject><subject>13/31</subject><subject>14/1</subject><subject>14/10</subject><subject>38/1</subject><subject>38/77</subject><subject>38/91</subject><subject>45/91</subject><subject>631/67/1990/283/1897</subject><subject>64/60</subject><subject>692/699/67/1990/283</subject><subject>82/1</subject><subject>82/58</subject><subject>96/106</subject><subject>96/31</subject><subject>Acute myeloid leukemia</subject><subject>Alcohol Oxidoreductases - metabolism</subject><subject>Antibodies</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Self Renewal - physiology</subject><subject>Cell self-renewal</subject><subject>Cyclin-dependent kinase 2</subject><subject>DNA (Cytosine-5-)-Methyltransferases - metabolism</subject><subject>DNA Methylation - physiology</subject><subject>DNA Methyltransferase 3A</subject><subject>DNA Modification Methylases - metabolism</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Humans</subject><subject>Immunology</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Life Sciences</subject><subject>Mass spectroscopy</subject><subject>MDS1 and EVI1 Complex Locus Protein - metabolism</subject><subject>Methyltransferase</subject><subject>Phosphorylation</subject><subject>Post-translation</subject><subject>Progenitor cells</subject><subject>Prognosis</subject><subject>Protein interaction</subject><subject>Serine</subject><subject>Serine - metabolism</subject><subject>Transcription</subject><subject>Transcription Factors - metabolism</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU1v1DAQhi0EotXSP8ABWeLCJWX8EX9ckMrSQqUWkChcLW8y2U2VtRc7adV_X2-3lNIDli2_8jwee-Yl5DWDQwbCvM-SSWYr4FCBAFvUM7LPQbJKGmOfP9J75CDnSyhDCOC1ekn2ijBcgN4nzfGvU0Y3q5jLSjeDH_sYqB_pDykUTbicyhFm2ocRk2-20Uyv-3FF5-PH74z60NJPX88vxNGd3KS4jls-49BVCQNe--EVedH5IePB_T4jP0-OL-ZfqrNvn0_nR2dVI7UcK2-gXljLURruuWy5MmCEtlp01jImPEIjFNRiYazsWjDKygYVMN5qXRsmZuTDLu9mWqyxbTCMyQ9uk_q1Tzcu-t79Gwn9yi3jldO1VqZ0dUbe3SdI8feEeXTrPjc4DD5gnLLjsuZWG8VVQd8-QS_jlEIpr1CalWlLu2eE76gmxZwTdg-fYeC2Nrqdja7Y6O5sdNtfvHlcxsOVP6YVQOyAXEJhienv2_9JewvXsqW_</recordid><startdate>20201020</startdate><enddate>20201020</enddate><creator>Paredes, Roberto</creator><creator>Kelly, James R.</creator><creator>Geary, Bethany</creator><creator>Almarzouq, Batool</creator><creator>Schneider, Marion</creator><creator>Pearson, Stella</creator><creator>Narayanan, Prakrithi</creator><creator>Williamson, Andrew</creator><creator>Lovell, Simon C.</creator><creator>Wiseman, Daniel H.</creator><creator>Chadwick, John A.</creator><creator>Jones, Nigel J.</creator><creator>Kustikova, Olga</creator><creator>Schambach, Axel</creator><creator>Garner, Terence</creator><creator>Amaral, Fabio M. 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R.</au><au>Pierce, Andrew</au><au>Stevens, Adam</au><au>Somervaille, Tim C. P.</au><au>Whetton, Anthony D.</au><au>Meyer, Stefan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2020-10-20</date><risdate>2020</risdate><volume>11</volume><issue>10</issue><spage>878</spage><epage>878</epage><pages>878-878</pages><artnum>878</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high
EVI1
expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). Wild-type EVI1 (EVI1-WT) with S436 available for phosphorylation, but not non-phosphorylatable EVI1-S436A, conferred haematopoietic progenitor cell self-renewal and was associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed reduced affinity to CtBP1, and CtBP1 showed reduced interaction with EVI1-WT compared with EVI1-S436A. The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. These data point to EVI1-S436 phosphorylation directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may be of therapeutic benefit when treating EVI1-driven leukaemia.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33082307</pmid><doi>10.1038/s41419-020-03099-0</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-2596-2738</orcidid><orcidid>https://orcid.org/0000-0002-1950-7325</orcidid><orcidid>https://orcid.org/0000-0002-2283-3690</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell death & disease, 2020-10, Vol.11 (10), p.878-878, Article 878 |
| issn | 2041-4889 2041-4889 |
| language | eng |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | 101/58 13/1 13/31 14/1 14/10 38/1 38/77 38/91 45/91 631/67/1990/283/1897 64/60 692/699/67/1990/283 82/1 82/58 96/106 96/31 Acute myeloid leukemia Alcohol Oxidoreductases - metabolism Antibodies Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Cell Self Renewal - physiology Cell self-renewal Cyclin-dependent kinase 2 DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation - physiology DNA Methyltransferase 3A DNA Modification Methylases - metabolism DNA-Binding Proteins - metabolism Humans Immunology Leukemia Leukemia, Myeloid, Acute - metabolism Life Sciences Mass spectroscopy MDS1 and EVI1 Complex Locus Protein - metabolism Methyltransferase Phosphorylation Post-translation Progenitor cells Prognosis Protein interaction Serine Serine - metabolism Transcription Transcription Factors - metabolism |
| title | EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-29T10%3A34%3A46IST&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=EVI1%20phosphorylation%20at%20S436%20regulates%20interactions%20with%20CtBP1%20and%20DNMT3A%20and%20promotes%20self-renewal&rft.jtitle=Cell%20death%20&%20disease&rft.au=Paredes,%20Roberto&rft.date=2020-10-20&rft.volume=11&rft.issue=10&rft.spage=878&rft.epage=878&rft.pages=878-878&rft.artnum=878&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/s41419-020-03099-0&rft_dat=%3Cproquest_pubme%3E2452978626%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=2471471903&rft_id=info:pmid/33082307&rfr_iscdi=true |