PUBLICATION
A BMP4-p38 MAPK signaling axis controls ISL1 protein stability and activity during cardiogenesis
- Authors
- Jing, Y., Ren, Y., Witzel, H.R., Dobreva, G.
- ID
- ZDB-PUB-210731-7
- Date
- 2021
- Source
- Stem Cell Reports 16(8): 1894-1905 (Journal)
- Registered Authors
- Dobreva, Gergana
- Keywords
- BMP signaling, ISL1, cardiac progenitor cells, cardiomyocyte differentiation, heart development, p38 MAPK, protein phosphorylation
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Bone Morphogenetic Protein 4/metabolism*
- Cell Differentiation/genetics
- Gene Expression Regulation, Developmental
- Heart/embryology
- LIM-Homeodomain Proteins/genetics
- LIM-Homeodomain Proteins/metabolism*
- Mice
- Mice, Knockout
- Myocardium/cytology
- Myocardium/metabolism*
- NIH 3T3 Cells
- Organogenesis/genetics
- Protein Stability
- Signal Transduction*
- Stem Cells/metabolism
- Transcription Factors/genetics
- Transcription Factors/metabolism*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism*
- p38 Mitogen-Activated Protein Kinases/metabolism*
- PubMed
- 34329593 Full text @ Stem Cell Reports
Citation
Jing, Y., Ren, Y., Witzel, H.R., Dobreva, G. (2021) A BMP4-p38 MAPK signaling axis controls ISL1 protein stability and activity during cardiogenesis. Stem Cell Reports. 16(8):1894-1905.
Abstract
During development, cells respond rapidly to intra- and intercellular signals, which induce signaling cascades regulating the activity of transcription factors at the transcriptional and/or post-translational level. The transcription factor ISL1 plays a key role in second heart field development and cardiac differentiation, and its mRNA levels are tightly regulated during cardiogenesis. Here, we show that a BMP-p38 MAPK signaling axis controls ISL1 protein function at the post-translational level. BMP-mediated activation of p38 MAPK leads to ISL1 phosphorylation at S269 by p38, which prevents ISL1 degradation and ensures its transcriptional activity during cardiogenesis. Interfering with p38 MAPK signaling leads to the degradation of ISL1 by the proteasome, resulting in defects in cardiomyocyte differentiation and impaired zebrafish and mouse heart morphogenesis and function. Given the critical role of the tight control of ISL1 activity during cardiac lineage diversification, modulation of BMP4-p38 MAPK signaling could direct differentiation into specific cardiac cell subpopulations.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping