Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/46022 http://dx.doi.org/10.1038/s41421-018-0024-3 |
Resumo: | PEAK1 is a newly described tyrosine kinase and scaffold protein that transmits integrin-mediated extracellular matrix (ECM) signals to facilitate cell movement and growth. While aberrant expression of PEAK1 has been linked to cancer progression, its normal physiological role in vertebrate biology is not known. Here we provide evidence that PEAK1 plays a central role in orchestrating new vessel formation in vertebrates. Deletion of the PEAK1 gene in zebrafish, mice, and human endothelial cells (ECs) induced severe defects in new blood vessel formation due to deficiencies in EC proliferation, survival, and migration. Gene transcriptional and proteomic analyses of PEAK1-deficient ECs revealed a significant loss of vascular endothelial growth factor receptor 2 (VEGFR2) mRNA and protein expression, as well as downstream signaling to its effectors, ERK, Akt, and Src kinase. PEAK1 regulates VEGFR2 expression by binding to and increasing the protein stability of the transcription factor GATA-binding protein 2 (GATA2), which controls VEGFR2 transcription. Importantly, PEAK1-GATA2-dependent VEGFR2 expression is mediated by EC adhesion to the ECM and is required for breast cancer-induced new vessel formation in mice. Also, elevated expression of PEAK1 and VEGFR2 mRNA are highly correlated in many human cancers including breast cancer. Together, our findings reveal a novel PEAK1-GATA2-VEGFR2 signaling axis that integrates cell adhesion and growth factor cues from the extracellular environment necessary for new vessel formation during vertebrate development and cancer. |
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Wang, HuaweiLapek, JohnFujimura, KenStrnadel, JanLiu, BeiGonzalez, David J.Zhang, WeiWatson, FeliciaYu, VickyLiu, ChaoMelo, Carina Muccilo [UNIFESP]Miller, Yury I.Elliott, Kathryn C.Cheresh, David A.Klemke, Richard L.2018-07-26T12:18:44Z2018-07-26T12:18:44Z2018Cell Discovery. London, v. 4, p. -, 2018.2056-5968http://repositorio.unifesp.br/handle/11600/46022http://dx.doi.org/10.1038/s41421-018-0024-3WOS000433282700001.pdf10.1038/s41421-018-0024-3WOS:000433282700001PEAK1 is a newly described tyrosine kinase and scaffold protein that transmits integrin-mediated extracellular matrix (ECM) signals to facilitate cell movement and growth. While aberrant expression of PEAK1 has been linked to cancer progression, its normal physiological role in vertebrate biology is not known. Here we provide evidence that PEAK1 plays a central role in orchestrating new vessel formation in vertebrates. Deletion of the PEAK1 gene in zebrafish, mice, and human endothelial cells (ECs) induced severe defects in new blood vessel formation due to deficiencies in EC proliferation, survival, and migration. Gene transcriptional and proteomic analyses of PEAK1-deficient ECs revealed a significant loss of vascular endothelial growth factor receptor 2 (VEGFR2) mRNA and protein expression, as well as downstream signaling to its effectors, ERK, Akt, and Src kinase. PEAK1 regulates VEGFR2 expression by binding to and increasing the protein stability of the transcription factor GATA-binding protein 2 (GATA2), which controls VEGFR2 transcription. Importantly, PEAK1-GATA2-dependent VEGFR2 expression is mediated by EC adhesion to the ECM and is required for breast cancer-induced new vessel formation in mice. Also, elevated expression of PEAK1 and VEGFR2 mRNA are highly correlated in many human cancers including breast cancer. Together, our findings reveal a novel PEAK1-GATA2-VEGFR2 signaling axis that integrates cell adhesion and growth factor cues from the extracellular environment necessary for new vessel formation during vertebrate development and cancer.NIHNCIAHANIGMS/NIHRay Thomas Edwards FoundationUniv Calif San Diego, Dept Pathol, La Jolla, CA 92093 USAUniv Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USAUniv Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USAUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USAUniv Fed Sao Paulo, Dept Biochem, Sao Paulo, SP, BrazilUniv Calif San Diego, Sanford Consortium Regenerat Med, La Jolla, CA 92093 USAComenius Univ, Jessenius Fac Med Martin, Dept Mol Med, Biomed Ctr Martin, Martin 03601, SlovakiaUniv Fed Sao Paulo, Dept Biochem, Sao Paulo, SP, BrazilNIH: CA182495NIH: CA184594NIH: CA097022NIH: HL135737NIH: CA050286NCI: CA180374AHA: 16POST27250126NIGMS/NIH: K12GM068524Web of ScienceengNature Publishing GroupPseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcriptioninfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000433282700001.pdfapplication/pdf7462437${dspace.ui.url}/bitstream/11600/46022/1/WOS000433282700001.pdf0f5a00f606efbeb52b6ec22a5f83fd65MD51open accessTEXTWOS000433282700001.pdf.txtWOS000433282700001.pdf.txtExtracted texttext/plain93743${dspace.ui.url}/bitstream/11600/46022/2/WOS000433282700001.pdf.txt4f25343c036b826626697b257cdb5475MD52open accessTHUMBNAILWOS000433282700001.pdf.jpgWOS000433282700001.pdf.jpgIM Thumbnailimage/jpeg7057${dspace.ui.url}/bitstream/11600/46022/4/WOS000433282700001.pdf.jpgeda26d2aab020250afdde059c449ee5cMD54open access11600/460222022-08-02 11:10:24.045open accessoai:repositorio.unifesp.br:11600/46022Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652022-08-02T14:10:24Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription |
title |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription |
spellingShingle |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription Wang, Huawei |
title_short |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription |
title_full |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription |
title_fullStr |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription |
title_full_unstemmed |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription |
title_sort |
Pseudopodium-enriched atypical kinase 1 mediates angiogenesis by modulating GATA2-dependent VEGFR2 transcription |
author |
Wang, Huawei |
author_facet |
Wang, Huawei Lapek, John Fujimura, Ken Strnadel, Jan Liu, Bei Gonzalez, David J. Zhang, Wei Watson, Felicia Yu, Vicky Liu, Chao Melo, Carina Muccilo [UNIFESP] Miller, Yury I. Elliott, Kathryn C. Cheresh, David A. Klemke, Richard L. |
author_role |
author |
author2 |
Lapek, John Fujimura, Ken Strnadel, Jan Liu, Bei Gonzalez, David J. Zhang, Wei Watson, Felicia Yu, Vicky Liu, Chao Melo, Carina Muccilo [UNIFESP] Miller, Yury I. Elliott, Kathryn C. Cheresh, David A. Klemke, Richard L. |
author2_role |
author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Wang, Huawei Lapek, John Fujimura, Ken Strnadel, Jan Liu, Bei Gonzalez, David J. Zhang, Wei Watson, Felicia Yu, Vicky Liu, Chao Melo, Carina Muccilo [UNIFESP] Miller, Yury I. Elliott, Kathryn C. Cheresh, David A. Klemke, Richard L. |
description |
PEAK1 is a newly described tyrosine kinase and scaffold protein that transmits integrin-mediated extracellular matrix (ECM) signals to facilitate cell movement and growth. While aberrant expression of PEAK1 has been linked to cancer progression, its normal physiological role in vertebrate biology is not known. Here we provide evidence that PEAK1 plays a central role in orchestrating new vessel formation in vertebrates. Deletion of the PEAK1 gene in zebrafish, mice, and human endothelial cells (ECs) induced severe defects in new blood vessel formation due to deficiencies in EC proliferation, survival, and migration. Gene transcriptional and proteomic analyses of PEAK1-deficient ECs revealed a significant loss of vascular endothelial growth factor receptor 2 (VEGFR2) mRNA and protein expression, as well as downstream signaling to its effectors, ERK, Akt, and Src kinase. PEAK1 regulates VEGFR2 expression by binding to and increasing the protein stability of the transcription factor GATA-binding protein 2 (GATA2), which controls VEGFR2 transcription. Importantly, PEAK1-GATA2-dependent VEGFR2 expression is mediated by EC adhesion to the ECM and is required for breast cancer-induced new vessel formation in mice. Also, elevated expression of PEAK1 and VEGFR2 mRNA are highly correlated in many human cancers including breast cancer. Together, our findings reveal a novel PEAK1-GATA2-VEGFR2 signaling axis that integrates cell adhesion and growth factor cues from the extracellular environment necessary for new vessel formation during vertebrate development and cancer. |
publishDate |
2018 |
dc.date.accessioned.fl_str_mv |
2018-07-26T12:18:44Z |
dc.date.available.fl_str_mv |
2018-07-26T12:18:44Z |
dc.date.issued.fl_str_mv |
2018 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
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article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Cell Discovery. London, v. 4, p. -, 2018. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/46022 http://dx.doi.org/10.1038/s41421-018-0024-3 |
dc.identifier.issn.none.fl_str_mv |
2056-5968 |
dc.identifier.file.none.fl_str_mv |
WOS000433282700001.pdf |
dc.identifier.doi.none.fl_str_mv |
10.1038/s41421-018-0024-3 |
dc.identifier.wos.none.fl_str_mv |
WOS:000433282700001 |
identifier_str_mv |
Cell Discovery. London, v. 4, p. -, 2018. 2056-5968 WOS000433282700001.pdf 10.1038/s41421-018-0024-3 WOS:000433282700001 |
url |
http://repositorio.unifesp.br/handle/11600/46022 http://dx.doi.org/10.1038/s41421-018-0024-3 |
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Nature Publishing Group |
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Nature Publishing Group |
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