Year: 2018
Type: article
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.
Source: iScience
Institutions: University of Washington, Howard Hughes Medical Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
Awards: G1639924075, Expansion of cardiac and hematopoietic progenitors by Wnt and Notch, G39800811, Experimental Pathology of Cardiovascular Disease, STEM CELLS AND CARDIOVASCULAR REPAIR, Cell-Based Cardiac Repair, G7471270566, G7999895773, Self Renewal and Differentiation of Human Embryonic Stem Cells, G8368187446, Diabetes Research Center
OpenAlex ID: W2797504131