Open AccessE rb B 4 Activated p38γ MAPK Isoform Mediates Early Cardiogenesis Through NK x2.5 in Human Pluripotent Stem Cells
Author(s) -
Ramachandra Chrishan J.A.,
Mehta Ashish,
Wong Philip,
Shim Winston
Publication year - 2016
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2223
Subject(s) - biology , microbiology and biotechnology , gene knockdown , induced pluripotent stem cell , mef2c , gene isoform , embryonic stem cell , downregulation and upregulation , p38 mitogen activated protein kinases , mapk/erk pathway , signal transduction , transcription factor , cell culture , genetics , gene
Activation of ErbB4 receptor signaling is instrumental in heart development, lack of which results in embryonic lethality. However, mechanism governing its intracellular signaling remains elusive. Using human pluripotent stem cells, we show that ErbB4 is critical for cardiogenesis whereby its genetic knockdown results in loss of cardiomyocytes. Phospho‐proteome profiling and Western blot studies attribute this loss to inactivation of p38γ MAPK isoform which physically interacts with NKx2.5 and GATA4 transcription factors. Post‐cardiomyocyte formation p38γ/NKx2.5 downregulation is followed by p38α/MEF2c upregulation suggesting stage‐specific developmental roles of p38 MAPK isoforms. Knockdown of p38γ MAPK similarly disrupts cardiomyocyte formation in spite of the presence of NKx2.5. Cell fractionation and NKx2.5 phosphorylation studies suggest inhibition of ErbB4‐p38γ signaling hinders NKx2.5 nuclear translocation during early cardiogenesis. This study reveals a novel pathway that directly links ErbB4 and p38γ to the transcriptional machinery of NKx2.5‐GATA4 complex which is critical for cardiomyocyte formation during mammalian heart development. S tem C ells 2016;34:288–298