2. Academic Validation
  3. ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells

ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells

  • iScience. 2018 Apr 27;2:88-100. doi: 10.1016/j.isci.2018.03.010.
Peter Hofsteen 1,  Aaron Mark Robitaille 2,  Nicholas Strash 3,  Nathan Palpant 3,  Randall T Moon 4,  Lil Pabon 3,  Charles E Murry 5
Affiliations

Affiliations

  • 1 Department 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. Electronic address: phofsteen@uw.edu.
  • 2 Department 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.
  • 3 Department 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.
  • 4 Department 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, USA.
  • 5 Department 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. Electronic address: murry@uw.edu.
PMID: 29888752 DOI: 10.1016/j.isci.2018.03.010
Abstract

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.

Figures