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

Abstract

Macrophage colony stimulating factor (MCSF) influences proliferation and survival of mononuclear phagocytes through the CSF-1 receptor. The DAP12 adaptor protein, which transduces signals emanating from various myeloid receptors, is critical for mononuclear phagocyte function. DAP12-mutant mice and humans show defects in osteoclasts and microglia and exhibit brain and bone abnormalities. Here, we demonstrated that DAP12 deficiency impairs MCSF-induced macrophage proliferation and survival in vitro. In addition, DAP12-deficient mice show fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerate myeloid cells inefficiently following BM transplantation. MCSF-CSF1-R signaling induced stabilization and nuclear translocation of β-catenin, which activates cell cycle genes. DAP12 was essential for phosphorylation and nuclear accumulation of β-catenin. These results outline a mechanistic explanation for the multiple defects in DAP12-deficient mononuclear phagocytes.

A TRPC1 Protein-dependent Pathway Regulates Osteoclast Formation and Function

“…One possibility is that I-mfa suppresses the survival and/or proliferation of early osteoclast progenitors in response to M-CSF. Interestingly, M-CSF signaling is essential for the proliferation and survival of these progenitors through the up-regulation of ␤-catenin mediated by the action of the Ca 2ϩ -sensitive Pyk2 tyrosine kinase (3). Therefore, we could envision a positive feedback loop whereby accumulated ␤-catenin could compete with TRPC1 for binding to I-mfa, relieving the I-mfa-mediated suppression of TRPC1 activity, thus allowing for Ca 2ϩ influx.…”

“…Subsequently, these precursors differentiate into multinucleated osteoclasts in a multistep process dependent on M-CSF and receptor activator of nuclear factor-B ligand (RANKL) (2). Both of these factors act through Ca 2ϩ signaling to induce downstream regulators of osteoclastogenesis such as nuclear factor of activated T cells c1 (NFATc1), NF-B, c-fos, ␤-catenin, and others (3,4). However, the molecular identity of the Ca 2ϩ channels essential for osteoclastogenesis is only recently starting to emerge.…”

CSF-1 Receptor Signaling in Myeloid Cells

“…The cytoplasmic domain of DAP12 contains immunoreceptor tyrosine-based activation motifs (ITAMs), which become phosphorylated in response to CSF-1R activation, recruiting and activating the cytosolic tyrosine kinase Syk, which activates the Pyk2 tyrosine kinase that phosphorylates b-catenin, triggering its nuclear translocation and activation of cell-cycle genes. The response is enhanced by DAP12-independent CSF-1R inhibition of b-catenin degradation (Otero et al 2009). DAP12 deficiency leads to impaired CSF-1R-mediated proliferation and survival, but does not affect differentiation (Nataf et al 2005;Otero et al 2009).…”

“…The response is enhanced by DAP12-independent CSF-1R inhibition of b-catenin degradation (Otero et al 2009). DAP12 deficiency leads to impaired CSF-1R-mediated proliferation and survival, but does not affect differentiation (Nataf et al 2005;Otero et al 2009). …”

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

“…It has been shown that Pyk, a tyrosine kinase, phosphorylates β-catenin at tyrosine residues [195,196]. This phosphorylation is associated with decreased attachment to Ecadherin and increased stability and nuclear translocation of β-catenin [197].…”