title: Reactive oxygen species regulate M-CSF-induced monocyte/macrophage proliferation through SHP1 oxidation.
abstract: Macrophage colony-stimulating factor (M-CSF) stimulation results in the production of reactive oxygen species (ROS) that participate in the proliferation of monocyte/macrophage. However, the molecular mechanisms whereby ROS modulate the signaling processes of M-CSF remain poorly defined. We report here that the redox-sensitive Src homology region 2 domain-containing phosphatase 1 (SHP1) is a critical regulator of M-CSF-mediated signaling in bone marrow monocyte/macrophage lineage cells (BMMs). Application of diphenylene iodonium (DPI) inhibited the responses of BMMs to M-CSF, including ROS production, cell proliferation, and phosphorylation of c-Fms as well as Akt kinase, but not of MAP kinases such as ERK, p38, and JNK. Dysregulation of SHP1 by overexpression or RNA interference in BMMs showed that SHP1 specifically regulates PI3 kinase (PI3K)/Akt signaling, but not MAP kinases in a redox-dependent manner, thereby regulating proliferation of BMMs through cyclins D1 and D2. These findings demonstrate that M-CSF-mediated ROS generation leads to SHP1 oxidation, which promotes cell proliferation through the PI3K/Akt-dependent signaling pathway.
authors.affiliation: Division of Life and Pharmaceutical Sciences, Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Han Kyoung
authors.initials: HK
authors.lastname: Choi
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Kim
authors.forename: Gil-Ja
authors.initials: GJ
authors.lastname: Jhon
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D056741:Cyclin D / Q000378:metabolism; D005822:Genetic Vectors; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D012190:Retroviridae / Q000472:pathogenicity; D015398:Signal Transduction; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D056741:Cyclin D; D009861:Onium Compounds; D017382:Reactive Oxygen Species; C007517:diphenyleneiodonium; D016173:Macrophage Colony-Stimulating Factor; D006861:Hydrogen Peroxide; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6