| First Author | Lee AW | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 22 | Pages | 4563-81 |
| PubMed ID | 21930791 | Mgi Jnum | J:178777 |
| Mgi Id | MGI:5300119 | Doi | 10.1128/MCB.05706-11 |
| Citation | Lee AW, et al. (2011) Gab2 promotes colony-stimulating factor 1-regulated macrophage expansion via alternate effectors at different stages of development. Mol Cell Biol 31(22):4563-81 |
| abstractText | Colony-stimulating factor 1 (CSF-1) receptor (CSF-1R, or macrophage CSF receptor [M-CSFR]) is the primary regulator of the proliferation, survival, and differentiation of mononuclear phagocytes (MNPs), but the critical CSF-1 signals for these functions are unclear. The scaffold protein Gab2 is a major tyrosyl phosphoprotein in the CSF-1R signaling network. Here we demonstrate that Gab2 deficiency results in profoundly defective expansion of CSF-1R-dependent MNP progenitors in the bone marrow, through decreased proliferation and survival. Reconstitution and phospho-flow studies show that downstream of CSF-1R, Gab2 uses phosphatidylinositol 3-kinase (PI3K)-Akt and extracellular signal-regulated kinase (Erk) to regulate MNP progenitor expansion. Unexpectedly, Gab2 ablation enhances Jun N-terminal protein kinase 1 (JNK1) phosphorylation in differentiated MNPs but reduces their proliferation; inhibition of JNK signaling or reduction of JNK1 levels restores proliferation. MNP recruitment to inflammatory sites and the corresponding bone marrow response is strongly impaired in Gab2-deficient mice. Our data provide genetic and biochemical evidence that CSF-1R, through Gab2, utilizes different effectors at different stages of MNP development to promote their expansion. |
