SCF/c-kit transactivates CXCR4-serine 339 phosphorylation through G protein-coupled receptor kinase 6 and regulates cardiac stem cell migration.

Abstract

C-kit positive cardiac stem cells (CSCs) have been shown to contribute to myocardial regeneration after infarction. Previously, we have shown that the c-kit ligand stem cell factor (SCF) can induce CSC migration into the infarcted area during myocardial infarction (MI). However, the precise mechanism involved is not fully understood. In this study, we found that CSCs also express C-X-C chemokine receptor type 4 (CXCR4), which is a typical member of the seven transmembrane-spanning G protein-coupled receptor (GPCR). In vitro, activation of c-kit signalling by SCF promotes migration of CSCs with increased phosphorylation of CXCR4-serine 339, p38 mitogen-activated protein kinase (p38 MAPK) and extracellular regulated protein kinases 1/2 (ERK1/2). Knockdown of CXCR4 expression by siRNA reduces SCF/c-kit-induced migration and downstream signalling. As previously reported, CXCR4-serine 339 phosphorylation is mainly regulated by GPCR kinase 6 (GRK6); thus, silencing of GRK6 expression by siRNA impairs CXCR4-serine 339 phosphorylation and migration of CSCs caused by SCF. In vivo, knockdown of GRK6 impairs the ability of CSCs to migrate into peri-infarcted areas. These results demonstrate that SCF-induced CSC migration is regulated by the transactivation of CXCR4-serine 339 phosphorylation, which is mediated by GRK6.

• Authors: Ke Zuo, Dong Kuang, Ying Wang, Yanli Xia, Weilin Tong, Xiaoyan Wang, Yaobin Chen, Yaqi Duan, Guoping Wang
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 26812 (06 01 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27245949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR4 protein, mouse
• RNA, Small Interfering
• Receptors, CXCR4
• Stem Cell Factor
• Phosphoserine
• Proto-Oncogene Proteins c-kit
• G-Protein-Coupled Receptor Kinases
• G-protein-coupled receptor kinase 6

Topics

• Adult Stem Cells (physiology)
• Animals
• Cells, Cultured
• Chemotaxis (physiology)
• Enzyme Activation
• Female
• G-Protein-Coupled Receptor Kinases (antagonists & inhibitors, genetics, physiology)
• HEK293 Cells
• Humans
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (pathology)
• Myocardium (cytology)
• Phosphorylation
• Phosphoserine (metabolism)
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-kit (physiology)
• RNA Interference
• RNA, Small Interfering (genetics)
• Receptors, CXCR4 (metabolism)
• Stem Cell Factor (physiology)
• Transcriptional Activation
• Transfection