ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells
Summary: Cardiac development requires coordinated biphasic regulation of the WNT/β-catenin signaling pathway. By intersecting gene expression and loss-of-function siRNA screens we identified Alpha Protein Kinase 2 (ALPK2) as a candidate negative regulator of WNT/β-catenin signaling in cardiogenesis....
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-04-01
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| Series: | iScience |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004218300191 |
| _version_ | 1818025456389062656 |
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| author | Peter Hofsteen Aaron Mark Robitaille Nicholas Strash Nathan Palpant Randall T. Moon Lil Pabon Charles E. Murry |
| author_facet | Peter Hofsteen Aaron Mark Robitaille Nicholas Strash Nathan Palpant Randall T. Moon Lil Pabon Charles E. Murry |
| author_sort | Peter Hofsteen |
| collection | DOAJ |
| description | Summary: Cardiac development requires coordinated biphasic regulation of the WNT/β-catenin signaling pathway. By intersecting gene expression and loss-of-function siRNA screens we identified Alpha Protein Kinase 2 (ALPK2) as a candidate negative regulator of WNT/β-catenin signaling in cardiogenesis. In differentiating human embryonic stem cells (hESCs), ALPK2 is highly induced as hESCs transition from mesoderm to cardiac progenitors. Using antisense knockdown and CRISPR/Cas9 mutagenesis in hESCs and zebrafish, we demonstrate that ALPK2 promotes cardiac function and cardiomyocyte differentiation. Quantitative phosphoproteomics, protein expression profiling, and β-catenin reporter assays demonstrate that loss of ALPK2 led to stabilization of β-catenin and increased WNT signaling. Furthermore, cardiac defects attributed to ALPK2 depletion can be rescued in a dose-dependent manner by direct inhibition of WNT signaling through the small molecule XAV939. Together, these results demonstrate that ALPK2 regulates β-catenin-dependent signaling during developmental commitment of cardiomyocytes. : Piscine Cardiology; Stem Cell Research; Developmental Biology Subject Areas: Piscine Cardiology, Stem Cell Research, Developmental Biology |
| first_indexed | 2024-12-10T04:16:24Z |
| format | Article |
| id | doaj.art-7af71fc9827042cf9fe6669709f29e0f |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-10T04:16:24Z |
| publishDate | 2018-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-7af71fc9827042cf9fe6669709f29e0f2022-12-22T02:02:34ZengElsevieriScience2589-00422018-04-01288100ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem CellsPeter Hofsteen0Aaron Mark Robitaille1Nicholas Strash2Nathan Palpant3Randall T. Moon4Lil Pabon5Charles E. Murry6Department of Pathology, School of Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA; Corresponding authorDepartment of Pharmacology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USADepartment of Pathology, School of Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USADepartment of Pathology, School of Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USADepartment of Pharmacology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98109, USADepartment of Pathology, School of Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USADepartment of Pathology, School of Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Department of Bioengineering, School of Medicine, University of Washington, Seattle, WA 98109, USA; Department of Medicine (Division of Cardiology), School of Medicine, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA; Corresponding authorSummary: Cardiac development requires coordinated biphasic regulation of the WNT/β-catenin signaling pathway. By intersecting gene expression and loss-of-function siRNA screens we identified Alpha Protein Kinase 2 (ALPK2) as a candidate negative regulator of WNT/β-catenin signaling in cardiogenesis. In differentiating human embryonic stem cells (hESCs), ALPK2 is highly induced as hESCs transition from mesoderm to cardiac progenitors. Using antisense knockdown and CRISPR/Cas9 mutagenesis in hESCs and zebrafish, we demonstrate that ALPK2 promotes cardiac function and cardiomyocyte differentiation. Quantitative phosphoproteomics, protein expression profiling, and β-catenin reporter assays demonstrate that loss of ALPK2 led to stabilization of β-catenin and increased WNT signaling. Furthermore, cardiac defects attributed to ALPK2 depletion can be rescued in a dose-dependent manner by direct inhibition of WNT signaling through the small molecule XAV939. Together, these results demonstrate that ALPK2 regulates β-catenin-dependent signaling during developmental commitment of cardiomyocytes. : Piscine Cardiology; Stem Cell Research; Developmental Biology Subject Areas: Piscine Cardiology, Stem Cell Research, Developmental Biologyhttp://www.sciencedirect.com/science/article/pii/S2589004218300191 |
| spellingShingle | Peter Hofsteen Aaron Mark Robitaille Nicholas Strash Nathan Palpant Randall T. Moon Lil Pabon Charles E. Murry ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells iScience |
| title | ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells |
| title_full | ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells |
| title_fullStr | ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells |
| title_full_unstemmed | ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells |
| title_short | ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells |
| title_sort | alpk2 promotes cardiogenesis in zebrafish and human pluripotent stem cells |
| url | http://www.sciencedirect.com/science/article/pii/S2589004218300191 |
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