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Mol Cell Biol. 2011 Nov;31(22):4563-81. doi: 10.1128/MCB.05706-11. Epub 2011 Sep 19.

Gab2 promotes colony-stimulating factor 1-regulated macrophage expansion via alternate effectors at different stages of development.

Author information

1
Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan, USA. awmlee@angelleelab.org

Abstract

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.

PMID:
21930791
PMCID:
PMC3209260
DOI:
10.1128/MCB.05706-11
[Indexed for MEDLINE]
Free PMC Article
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