Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin

Otero, K. et al. 2009. Nature Immunology 10: 734-744.

Speaker: 陳奐勻                                                         Time: 15:10~16:00, Oct 7, 2009

Commentator: 徐麗君老師                                               Place: Room 601

Abstract:

Macrophage colony stimulating factor (M-CSF) was first defined by their abilities to generate in vitro colonies of mature myeloid cells. The effects of CSF-1 are mediated by the CSF-1 receptor tyrosine kinase (CSF-1R), through autophosphorylation of CSF-1R and the subsequent phosphorylation of downstream molecules. Triggering this phosphorylation cascade increases gene transcription and protein translation, leading to the survival, proliferation and differentiation of target cells. DAP12 is an adaptor protein associated with several myeloid and lymphocyte receptors. After engagement of the associated receptor, the DAP12 ITAM is phosphorylated and acts as a docking site for the protein tyrosine kinases Syk, which activate downstream signaling enzymes to induce cell activation. In this study, the authors demonstrated that DAP12 is essential for CSF-1R signaling, specifically for enhancing the proliferation and survival of macrophages in response to M-CSF. DAP12-deficient macrophages proliferated poorly in response to M-CSF and did not survive in suboptimal amounts of M-CSF in vitro. DAP12-deficient progenitors regenerated myeloid cells inefficiently after bone marrow transplantation. M-CSF also increase β-catenin, which acts a coactivator of the transcription factors to induce the transcription of genes in the cell cycle. Mechanistically, DAP12 facilitated Pyk2-mediated tyrosine phosphorylation and subsequent nuclear translocation of β-catenin, which activated genes expression involved in the cell cycle. Altogether, our identification of a link among M-CSF, the DAP12 ITAM and β-catenin has demonstrated a signaling network that regulates the proliferation and survival of myeloid cells.

References:

1. McVicar, D. W. et al. 2009. CSF-1R, DAP12 and β-catenin: a ménage à trios. Nature Immunology 7: 681-683.

2. Lanier, L. L. et al. 2009. DAP10- and DAP12-associated receptors in innate immunity. Immunological Reviews 227:150-160.