Deficiency of SHP1 leads to sustained and increased ERK activation in mast cells, thereby inhibiting IL-3-dependent proliferation and cell death

• Published in: Molecular immunology 2011-01, Vol.48 (4), p.472-480
• Main Authors: Nakata, Kazuko, Suzuki, Yoshihiro, Inoue, Toshio, Ra, Chisei, Yakura, Hidetaka, Mizuno, Kazuya
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biocatalysis - drug effects; Bone Marrow Cells - cytology; Cell Death - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; enzyme activation; Enzyme Activation - drug effects; enzyme activity; enzyme inhibition; ERK; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Flavonoids - pharmacology; IL-3; interleukin-3; Interleukin-3 - pharmacology; Mast cells; Mast Cells - cytology; Mast Cells - drug effects; Mast Cells - enzymology; Mice; mitogen-activated protein kinase; mitogen-activated protein kinase kinase; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; protein-tyrosine-phosphatase; receptors; SHP-1; signal transduction
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2010.10.001

SHP-1 plays an important role for the regulation of signaling from various hematopoietic cell receptors. In this study, we examined IL-3-induced cell proliferation and IL-3 depletion-induced apoptosis in bone marrow-derived mast cells (BMMC) established from motheaten (me) that lack SHP-1 expression, viable motheaten (mev) expressing phosphatase-deficient SHP-1, and wild-type (WT) mice. When BMMC were stimulated with IL-3, increased ERK activation was evident in resting state and sustained in me-BMMC relative to WT-BMMC. ERK is known to be involved in the regulation of cell proliferation and apoptosis in some cells. In accordance with sustained ERK activation, apoptosis was decreased in me- and mev-BMMC compared with WT-BMMC. In contrast to the predicted role of ERK as a pro-survival molecule, IL-3-induced cell proliferation was much lower in me- and mev-BMMC than WT-BMMC. Stimulation with lower concentration of IL-3 or addition of PD98059, a MEK inhibitor, to the culture resulted in the suppression of decreased apoptosis and cell proliferation in me- and mev-BMMC. Collectively, these results suggest that SHP-1 positively regulates IL-3-dependent mast cell proliferation and apoptosis by inhibiting ERK activity through its phosphatase activity. Furthermore, our results indicate that ERK would act as a negative regulator for cell proliferation and induce apoptosis when its activity is highly increased.