Phosphorylation of ΔNp63α via a novel TGFβ/ALK5 signaling mechanism mediates the anti-clonogenic effects of TGFβ
Genetic analysis of TP63 implicates ΔNp63 isoforms in preservation of replicative capacity and cellular lifespan within adult stem cells. ΔNp63α is also an oncogene and survival factor that mediates therapeutic resistance in squamous carcinomas. These diverse activities are the result of genetic and...
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| Veröffentlicht in: | PloS one 2012-11, Vol.7 (11), p.e50066 |
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| creator | Cherukuri, Pratima DeCastro, Andrew J Balboni, Amanda L Downey, Sondra L Liu, Jennifer Y Hutchinson, Justine A DiRenzo, James |
| description | Genetic analysis of TP63 implicates ΔNp63 isoforms in preservation of replicative capacity and cellular lifespan within adult stem cells. ΔNp63α is also an oncogene and survival factor that mediates therapeutic resistance in squamous carcinomas. These diverse activities are the result of genetic and functional interactions between TP63 and an array of morphogenic and morphostatic signals that govern tissue and tumor stasis, mitotic polarity, and cell fate; however the cellular signals that account for specific functions of TP63 are incompletely understood. To address this we sought to identify signaling pathways that regulate expression, stability or activity of ΔNp63α. An siRNA-based screen of the human kinome identified the Type 1 TGFβ receptor, ALK5, as the kinase required for phosphorylation of ΔNp63α at Serine 66/68 (S66/68). This activity is TGFβ-dependent and sensitive to either ALK5-directed siRNA or the ALK5 kinase inhibitor A83-01. Mechanistic studies support a model in which ALK5 is proteolytically cleaved at the internal juxtamembrane region resulting in the translocation of the C-terminal ALK5-intracellular kinase domain (ALK5(IKD)). In this study, we demonstrate that ALK5-mediated phosphorylation of ΔNp63α is required for the anti-clonogenic effects of TGFΒ and ectopic expression of ALK5(IKD) mimics these effects. Finally, we present evidence that ultraviolet irradiation-mediated phosphorylation of ΔNp63α is sensitive to ALK5 inhibitors. These findings identify a non-canonical TGFβ-signaling pathway that mediates the anti-clonogenic effects of TGFβ and the effects of cellular stress via ΔNp63α phosphorylation. |
| doi_str_mv | 10.1371/journal.pone.0050066 |
| format | Article |
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ΔNp63α is also an oncogene and survival factor that mediates therapeutic resistance in squamous carcinomas. These diverse activities are the result of genetic and functional interactions between TP63 and an array of morphogenic and morphostatic signals that govern tissue and tumor stasis, mitotic polarity, and cell fate; however the cellular signals that account for specific functions of TP63 are incompletely understood. To address this we sought to identify signaling pathways that regulate expression, stability or activity of ΔNp63α. An siRNA-based screen of the human kinome identified the Type 1 TGFβ receptor, ALK5, as the kinase required for phosphorylation of ΔNp63α at Serine 66/68 (S66/68). This activity is TGFβ-dependent and sensitive to either ALK5-directed siRNA or the ALK5 kinase inhibitor A83-01. Mechanistic studies support a model in which ALK5 is proteolytically cleaved at the internal juxtamembrane region resulting in the translocation of the C-terminal ALK5-intracellular kinase domain (ALK5(IKD)). In this study, we demonstrate that ALK5-mediated phosphorylation of ΔNp63α is required for the anti-clonogenic effects of TGFΒ and ectopic expression of ALK5(IKD) mimics these effects. Finally, we present evidence that ultraviolet irradiation-mediated phosphorylation of ΔNp63α is sensitive to ALK5 inhibitors. These findings identify a non-canonical TGFβ-signaling pathway that mediates the anti-clonogenic effects of TGFβ and the effects of cellular stress via ΔNp63α phosphorylation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0050066</identifier><identifier>PMID: 23166821</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Biology ; Cancer ; Carcinoma ; Cell cycle ; Cell fate ; Cell survival ; Cells, Cultured ; Cellular stress response ; Colony-Forming Units Assay ; DNA Primers - genetics ; Ectopic expression ; Enzyme inhibitors ; Gene expression ; Genetic analysis ; Humans ; Irradiation ; Isoforms ; Kinases ; Life span ; Localization ; Medicine ; Models, Biological ; Pharmacology ; Phosphorylation ; Polarity ; Preservation ; Protein-Serine-Threonine Kinases - metabolism ; Receptors, Transforming Growth Factor beta - metabolism ; Resistance factors ; RNA, Small Interfering - genetics ; Rodents ; Senescence ; Serine ; Signal transduction ; Signal Transduction - genetics ; Signaling ; siRNA ; Stem cells ; Studies ; Survival factor ; Toxicology ; Transcription Factors - metabolism ; Transfection ; Transforming Growth Factor beta - metabolism ; Translocation ; Tumor Suppressor Proteins - metabolism ; Ultraviolet radiation</subject><ispartof>PloS one, 2012-11, Vol.7 (11), p.e50066</ispartof><rights>2012 Cherukuri et al. 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ΔNp63α is also an oncogene and survival factor that mediates therapeutic resistance in squamous carcinomas. These diverse activities are the result of genetic and functional interactions between TP63 and an array of morphogenic and morphostatic signals that govern tissue and tumor stasis, mitotic polarity, and cell fate; however the cellular signals that account for specific functions of TP63 are incompletely understood. To address this we sought to identify signaling pathways that regulate expression, stability or activity of ΔNp63α. An siRNA-based screen of the human kinome identified the Type 1 TGFβ receptor, ALK5, as the kinase required for phosphorylation of ΔNp63α at Serine 66/68 (S66/68). This activity is TGFβ-dependent and sensitive to either ALK5-directed siRNA or the ALK5 kinase inhibitor A83-01. Mechanistic studies support a model in which ALK5 is proteolytically cleaved at the internal juxtamembrane region resulting in the translocation of the C-terminal ALK5-intracellular kinase domain (ALK5(IKD)). In this study, we demonstrate that ALK5-mediated phosphorylation of ΔNp63α is required for the anti-clonogenic effects of TGFΒ and ectopic expression of ALK5(IKD) mimics these effects. Finally, we present evidence that ultraviolet irradiation-mediated phosphorylation of ΔNp63α is sensitive to ALK5 inhibitors. These findings identify a non-canonical TGFβ-signaling pathway that mediates the anti-clonogenic effects of TGFβ and the effects of cellular stress via ΔNp63α phosphorylation.</description><subject>Biology</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Cell cycle</subject><subject>Cell fate</subject><subject>Cell survival</subject><subject>Cells, Cultured</subject><subject>Cellular stress response</subject><subject>Colony-Forming Units Assay</subject><subject>DNA Primers - genetics</subject><subject>Ectopic expression</subject><subject>Enzyme inhibitors</subject><subject>Gene expression</subject><subject>Genetic analysis</subject><subject>Humans</subject><subject>Irradiation</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Life span</subject><subject>Localization</subject><subject>Medicine</subject><subject>Models, Biological</subject><subject>Pharmacology</subject><subject>Phosphorylation</subject><subject>Polarity</subject><subject>Preservation</subject><subject>Protein-Serine-Threonine Kinases - 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ΔNp63α is also an oncogene and survival factor that mediates therapeutic resistance in squamous carcinomas. These diverse activities are the result of genetic and functional interactions between TP63 and an array of morphogenic and morphostatic signals that govern tissue and tumor stasis, mitotic polarity, and cell fate; however the cellular signals that account for specific functions of TP63 are incompletely understood. To address this we sought to identify signaling pathways that regulate expression, stability or activity of ΔNp63α. An siRNA-based screen of the human kinome identified the Type 1 TGFβ receptor, ALK5, as the kinase required for phosphorylation of ΔNp63α at Serine 66/68 (S66/68). This activity is TGFβ-dependent and sensitive to either ALK5-directed siRNA or the ALK5 kinase inhibitor A83-01. Mechanistic studies support a model in which ALK5 is proteolytically cleaved at the internal juxtamembrane region resulting in the translocation of the C-terminal ALK5-intracellular kinase domain (ALK5(IKD)). In this study, we demonstrate that ALK5-mediated phosphorylation of ΔNp63α is required for the anti-clonogenic effects of TGFΒ and ectopic expression of ALK5(IKD) mimics these effects. Finally, we present evidence that ultraviolet irradiation-mediated phosphorylation of ΔNp63α is sensitive to ALK5 inhibitors. These findings identify a non-canonical TGFβ-signaling pathway that mediates the anti-clonogenic effects of TGFβ and the effects of cellular stress via ΔNp63α phosphorylation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23166821</pmid><doi>10.1371/journal.pone.0050066</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Biology Cancer Carcinoma Cell cycle Cell fate Cell survival Cells, Cultured Cellular stress response Colony-Forming Units Assay DNA Primers - genetics Ectopic expression Enzyme inhibitors Gene expression Genetic analysis Humans Irradiation Isoforms Kinases Life span Localization Medicine Models, Biological Pharmacology Phosphorylation Polarity Preservation Protein-Serine-Threonine Kinases - metabolism Receptors, Transforming Growth Factor beta - metabolism Resistance factors RNA, Small Interfering - genetics Rodents Senescence Serine Signal transduction Signal Transduction - genetics Signaling siRNA Stem cells Studies Survival factor Toxicology Transcription Factors - metabolism Transfection Transforming Growth Factor beta - metabolism Translocation Tumor Suppressor Proteins - metabolism Ultraviolet radiation |
| title | Phosphorylation of ΔNp63α via a novel TGFβ/ALK5 signaling mechanism mediates the anti-clonogenic effects of TGFβ |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T16%3A20%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phosphorylation%20of%20%CE%94Np63%CE%B1%20via%20a%20novel%20TGF%CE%B2/ALK5%20signaling%20mechanism%20mediates%20the%20anti-clonogenic%20effects%20of%20TGF%CE%B2&rft.jtitle=PloS%20one&rft.au=Cherukuri,%20Pratima&rft.date=2012-11-16&rft.volume=7&rft.issue=11&rft.spage=e50066&rft.pages=e50066-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0050066&rft_dat=%3Cproquest_plos_%3E2944507531%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1326746538&rft_id=info:pmid/23166821&rft_doaj_id=oai_doaj_org_article_5ee5fcfb2f4f4a96b689e85ae204992a&rfr_iscdi=true |