PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression

Abstract

Enhancing cardiomyocyte survival is crucial to blunt deterioration of myocardial structure and function following pathological damage. PIM1 (Proviral Insertion site in Murine leukemia virus (PIM) kinase 1) is a cardioprotective serine threonine kinase that promotes cardiomyocyte survival and antagonizes senescence through multiple concurrent molecular signaling cascades. In hematopoietic stem cells, PIM1 interacts with the receptor tyrosine kinase c-Kit upstream of the ERK (Extracellular signal-Regulated Kinase) and Akt signaling pathways involved in cell proliferation and survival. The relationship between PIM1 and c-Kit activity has not been explored in the myocardial context. This study delineates the interaction between PIM1 and c-Kit leading to enhanced protection of cardiomyocytes from stress. Elevated c-Kit expression is induced in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1. Co-immunoprecipitation and proximity ligation assay reveal protein–protein interaction between PIM1 and c-Kit. Following treatment with Stem Cell Factor, PIM1-overexpressing cardiomyocytes display elevated ERK activity consistent with c-Kit receptor activation. Functionally, elevated c-Kit expression confers enhanced protection against oxidative stress in vitro. This study identifies the mechanistic relationship between PIM1 and c-Kit in cardiomyocytes, demonstrating another facet of cardioprotection regulated by PIM1 kinase.

Genetics of Myocardial Interstitial Fibrosis in the Human Heart and Association with Disease

“…We provide further evidence for the role of CAMK2D in pathologic cardiac remodeling and fibrosis 52,53 via association of CAMK2D with increased myocardial T1 time. Additionally PIM1 , 54 NRP-1 , 41,42 and ACP1 40 have been shown to play a role in myocardial fibrosis and were implicated in our study results.…”

Dual data and motif clustering improves the modeling and interpretation of phosphoproteomic data

“…Interestingly, the c-MET ligand HGF is more abundant in EGFR WT samples ( Figure 6E ). Moreover, activation of the KIT receptor, which can also mediate bypass resistance to targeted therapies and is enriched in EGFR WT samples, is reportedly regulated, at least in part, by PIM1 ( An et al, 2016 ; Dziadziuszko et al, 2016 ; Ebeid et al, 2020 ) ( Figures 6D and 6E ). In total, our analysis identifies a consistent association between EGFR activity with established and previously unknown signaling mechanisms.…”

Cell-Based and Selected Cell-Free Therapies for Myocardial Infarction: How Do They Compare to the Current Treatment Options?

“…Pim1 inhibits the phosphorylation of the TGFβ pathway downstream effectors (Smad 2 and Smad3), thus preventing telomerase repression. This critical finding can contribute to implementing novel targets to enhance the lifespan of grafted cells [ 106 ]. Another extensively investigated way to boost the therapeutic effect of transplanted cells is combining different stem cell populations and applying preconditioned media [ 107 ].…”