The role of Src family kinases in mediating M-CSF receptor signaling and monocytic cell survival

Yijie Wang,Clay B Marsh,Melissa G Piper

doi:10.4236/abb.2012.35077

Abstract

Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role in regulating M-CSF-induced monocyte survival. We observed that M-CSF promoted c-Src activation in monocytes and MDMs in a time-dependent manner. Src inhibitors reduced M-CSF-mediated phosphorylation of the M-CSF receptor (M-CSFR), Akt, Erk1/2, and p38 MAPK. We also observed that Src directly phosphorylated the M-CSFR. Notably, the inhibitors blocked phosphorylation of specific tyrosine residues within the M-CSFR. We further demonstrated that the Src inhibitor, PP2, attenuated M-CSF-induced NF-κB activation and M-CSF-induced monocyte survival. These findings indicated that Src family kinases mediate monocyte survival through the regulation of receptor phosphorylation and modulation of downstream signaling events. Thus, we predict that targeting Src family kinases may have therapeutic implication in inflammatory diseases.

Highlights

Monocytes are derived from bone marrow progenitor cells
We hypothesized that Src family kinases are involved in M-CSF-regulated survival pathways in both monocytes and macrophages
Since Src family kinases are tyrosine phosphorylated following M-CSF stimulation in fibroblast cell lines overexpressing c-Fms [22], we first examined whether M-CSF directly activated c-Src as proximal kinase, in primary human monocytes or Monocyte-Derived Macrophages (MDMs)

Summary

Introduction

Monocytes are derived from bone marrow progenitor cells. A monocyte’s lifespan is 24 - 48 hours [1]. When a monocyte encounters specific growth factors, inflammatory cytokines or bacterial components, the monocyte enters the tissue and differentiates into a specialized tissue macrophage [2,3]. Macrophage colony-stimulating factor (MCSF) is important in promoting maturation of monocytes to macrophages as well as the survival of both cell types [4,5]. Survival of monocytes and macrophages occurs through the activation of Akt, Erk, p38 and JNK [6,7,8]. We reported that M-CSF activates Akt by suppressing caspase-3 and caspase-9 activity [5]

Methods

Results

Conclusion