Journal
ISCIENCE
Volume 2, Issue -, Pages 88-+Publisher
CELL PRESS
DOI: 10.1016/j.isci.2018.03.010
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Funding
- Experimental Pathology of Cardiovascular Disease, NIH [T32 HL007312]
- University of Washington's Proteomics Resource [UWPR95794]
- NIH [U01 HL100405, P01 GM081619, R01 HL084642, P01 HL094374]
- Foundation Leducq Transatlantic Network of Excellence
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Cardiac development requires coordinated biphasic regulation of the WNT/beta-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/beta-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 beta-catenin reporter assays demonstrate that loss of ALPK2 led to stabilization of beta-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 beta-catenin-dependent signaling during developmental commitment of cardiomyocytes.
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