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

Angel W. Lee, Yingwei Mao, Josef M. Penninger, Soojie Yu

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4563-4581
Number of pages19
JournalMolecular and cellular biology
Volume31
Issue number22
DOIs
StatePublished - Nov 2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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