Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK
The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb prot...
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| Veröffentlicht in: | Genes & development 2004-04, Vol.18 (7), p.816-829 |
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| creator | Kanei-Ishii, Chie Ninomiya-Tsuji, Jun Tanikawa, Jun Nomura, Teruaki Ishitani, Tohru Kishida, Satoshi Kokura, Kenji Kurahashi, Toshihiro Ichikawa-Iwata, Emi Kim, Yongsok Matsumoto, Kunihiro Ishii, Shunsuke |
| description | The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps. |
| doi_str_mv | 10.1101/gad.1170604 |
| format | Article |
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However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.1170604</identifier><identifier>PMID: 15082531</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Animals ; Carrier Proteins - metabolism ; Chloramphenicol O-Acetyltransferase - metabolism ; Down-Regulation ; Glutathione Transferase - metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Leukemia, Myeloid - metabolism ; MAP Kinase Kinase Kinases - antagonists & inhibitors ; MAP Kinase Kinase Kinases - genetics ; MAP Kinase Kinase Kinases - metabolism ; Mice ; Mitogen-Activated Protein Kinases - metabolism ; Mitogens ; Nuclear Proteins - metabolism ; Phosphorylation ; Precipitin Tests ; Protein-Serine-Threonine Kinases - metabolism ; Protein-Tyrosine Kinases - metabolism ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-myb - antagonists & inhibitors ; Proto-Oncogene Proteins c-myb - metabolism ; Research Papers ; RNA, Small Interfering - pharmacology ; Saccharomyces cerevisiae ; Signal Transduction ; Two-Hybrid System Techniques ; Ubiquitin ; Wnt Proteins ; Wnt1 Protein ; Zebrafish Proteins</subject><ispartof>Genes & development, 2004-04, Vol.18 (7), p.816-829</ispartof><rights>Copyright © 2004, Cold Spring Harbor Laboratory Press 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-b46ce127f84d9e2e53472878dd6f8cbb0129aac8ed719c8f2216a262174d17cd3</citedby><cites>FETCH-LOGICAL-c475t-b46ce127f84d9e2e53472878dd6f8cbb0129aac8ed719c8f2216a262174d17cd3</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/PMC387421/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC387421/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15082531$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanei-Ishii, Chie</creatorcontrib><creatorcontrib>Ninomiya-Tsuji, Jun</creatorcontrib><creatorcontrib>Tanikawa, Jun</creatorcontrib><creatorcontrib>Nomura, Teruaki</creatorcontrib><creatorcontrib>Ishitani, Tohru</creatorcontrib><creatorcontrib>Kishida, Satoshi</creatorcontrib><creatorcontrib>Kokura, Kenji</creatorcontrib><creatorcontrib>Kurahashi, Toshihiro</creatorcontrib><creatorcontrib>Ichikawa-Iwata, Emi</creatorcontrib><creatorcontrib>Kim, Yongsok</creatorcontrib><creatorcontrib>Matsumoto, Kunihiro</creatorcontrib><creatorcontrib>Ishii, Shunsuke</creatorcontrib><title>Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps.</description><subject>Animals</subject><subject>Carrier Proteins - metabolism</subject><subject>Chloramphenicol O-Acetyltransferase - metabolism</subject><subject>Down-Regulation</subject><subject>Glutathione Transferase - metabolism</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Leukemia, Myeloid - metabolism</subject><subject>MAP Kinase Kinase Kinases - antagonists & inhibitors</subject><subject>MAP Kinase Kinase Kinases - genetics</subject><subject>MAP Kinase Kinase Kinases - metabolism</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Mitogens</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Precipitin Tests</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-myb - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-myb - metabolism</subject><subject>Research Papers</subject><subject>RNA, Small Interfering - pharmacology</subject><subject>Saccharomyces cerevisiae</subject><subject>Signal Transduction</subject><subject>Two-Hybrid System Techniques</subject><subject>Ubiquitin</subject><subject>Wnt Proteins</subject><subject>Wnt1 Protein</subject><subject>Zebrafish Proteins</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb1PHDEQxS0UFA5IlT5ylSYs8Xi9_ihSIMSX7gIUIDosr-09HO3ZF3sP6f57Fu6UhCrFaGY0vzd60kPoM5BjAALf58aNgyCcsB00gYapqmFCfEATIhWpVM3VHtov5RchI8P5R7QHDZG0qWGCHh_iUAEuYR5Nj0N0K-sLXj6lMlZe92YIKWITHXZ-no3b7KnDtvq5bvEyp8GHiJ-DwXcnUzjCl1e3U3r0prieTQ_Rbmf64j9t-wG6Pz-7O72sZjcXV6cns8oy0QxVy7j1QEUnmVOe-qZmgkohneOdtG1LgCpjrPROgLKyoxS4oZyCYA6EdfUB-rH5u1y1C--sj0M2vV7msDB5rZMJ-v0lhic9T8-6loJRGPVft_qcfq98GfQiFOv73kSfVkULkLTm0PwXBKEaRTkbwW8b0OZUSvbdHzNA9GtuesxNb3Mb6S__-v_LboOqXwAH1pKr</recordid><startdate>20040401</startdate><enddate>20040401</enddate><creator>Kanei-Ishii, Chie</creator><creator>Ninomiya-Tsuji, Jun</creator><creator>Tanikawa, Jun</creator><creator>Nomura, Teruaki</creator><creator>Ishitani, Tohru</creator><creator>Kishida, Satoshi</creator><creator>Kokura, Kenji</creator><creator>Kurahashi, Toshihiro</creator><creator>Ichikawa-Iwata, Emi</creator><creator>Kim, Yongsok</creator><creator>Matsumoto, Kunihiro</creator><creator>Ishii, Shunsuke</creator><general>Cold Spring Harbor Laboratory Press</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>7TM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20040401</creationdate><title>Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK</title><author>Kanei-Ishii, Chie ; Ninomiya-Tsuji, Jun ; Tanikawa, Jun ; Nomura, Teruaki ; Ishitani, Tohru ; Kishida, Satoshi ; Kokura, Kenji ; Kurahashi, Toshihiro ; Ichikawa-Iwata, Emi ; Kim, Yongsok ; Matsumoto, Kunihiro ; Ishii, Shunsuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-b46ce127f84d9e2e53472878dd6f8cbb0129aac8ed719c8f2216a262174d17cd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Carrier Proteins - metabolism</topic><topic>Chloramphenicol O-Acetyltransferase - metabolism</topic><topic>Down-Regulation</topic><topic>Glutathione Transferase - metabolism</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Leukemia, Myeloid - metabolism</topic><topic>MAP Kinase Kinase Kinases - antagonists & inhibitors</topic><topic>MAP Kinase Kinase Kinases - genetics</topic><topic>MAP Kinase Kinase Kinases - metabolism</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Mitogens</topic><topic>Nuclear Proteins - metabolism</topic><topic>Phosphorylation</topic><topic>Precipitin Tests</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-myb - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-myb - metabolism</topic><topic>Research Papers</topic><topic>RNA, Small Interfering - pharmacology</topic><topic>Saccharomyces cerevisiae</topic><topic>Signal Transduction</topic><topic>Two-Hybrid System Techniques</topic><topic>Ubiquitin</topic><topic>Wnt Proteins</topic><topic>Wnt1 Protein</topic><topic>Zebrafish Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kanei-Ishii, Chie</creatorcontrib><creatorcontrib>Ninomiya-Tsuji, Jun</creatorcontrib><creatorcontrib>Tanikawa, Jun</creatorcontrib><creatorcontrib>Nomura, Teruaki</creatorcontrib><creatorcontrib>Ishitani, Tohru</creatorcontrib><creatorcontrib>Kishida, Satoshi</creatorcontrib><creatorcontrib>Kokura, Kenji</creatorcontrib><creatorcontrib>Kurahashi, Toshihiro</creatorcontrib><creatorcontrib>Ichikawa-Iwata, Emi</creatorcontrib><creatorcontrib>Kim, Yongsok</creatorcontrib><creatorcontrib>Matsumoto, Kunihiro</creatorcontrib><creatorcontrib>Ishii, Shunsuke</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kanei-Ishii, Chie</au><au>Ninomiya-Tsuji, Jun</au><au>Tanikawa, Jun</au><au>Nomura, Teruaki</au><au>Ishitani, Tohru</au><au>Kishida, Satoshi</au><au>Kokura, Kenji</au><au>Kurahashi, Toshihiro</au><au>Ichikawa-Iwata, Emi</au><au>Kim, Yongsok</au><au>Matsumoto, Kunihiro</au><au>Ishii, Shunsuke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2004-04-01</date><risdate>2004</risdate><volume>18</volume><issue>7</issue><spage>816</spage><epage>829</epage><pages>816-829</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>15082531</pmid><doi>10.1101/gad.1170604</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Carrier Proteins - metabolism Chloramphenicol O-Acetyltransferase - metabolism Down-Regulation Glutathione Transferase - metabolism Humans Intracellular Signaling Peptides and Proteins Leukemia, Myeloid - metabolism MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - genetics MAP Kinase Kinase Kinases - metabolism Mice Mitogen-Activated Protein Kinases - metabolism Mitogens Nuclear Proteins - metabolism Phosphorylation Precipitin Tests Protein-Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-myb - antagonists & inhibitors Proto-Oncogene Proteins c-myb - metabolism Research Papers RNA, Small Interfering - pharmacology Saccharomyces cerevisiae Signal Transduction Two-Hybrid System Techniques Ubiquitin Wnt Proteins Wnt1 Protein Zebrafish Proteins |
| title | Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK |
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