Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Abstract

Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x L expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…[41][42][43][44] The correlation between Akt activity and HK-II expression suggest the transcriptional regulation of HK-II by Akt, which has been supported by many studies. Insulin treatment increases HK-II mRNA and protein in various cell types and the increase is blocked by inhibition of PI3K, an upstream kinase of Akt, as well as inhibition of mTORC1, suggesting Akt/mTORC1 contribution 44,[46][47][48][49][50][51] (Figure 2). Hyperactivity of mTORC1 is sufficient to increase HK-II expression 52 and a recent comprehensive and unbiased analysis also supports mTORC1-mediated HK-II upregulation and further demonstrated that mTORC1 signaling activates the genes encoding nearly every step of glycolysis.…”

Colony-stimulating factor-1–induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages

“…Class I PI3Ks play an essential role at various stages of hematopoietic cell differentiation. 32,33 In normal human peripheral blood monocytes, PI3K regulates differentiation through activation of AKT and hexokinase II-mediated glycolysis, 34,35 and AKT activation was proposed to up-regulate Mcl-1 to prevent caspase-dependent cell death. 36 Here, we show that suppression of AKT1 or PI3K in human primary monocytes actually prevents the activation of caspases required for CSF-1-induced differentiation into macrophages.…”

ERK5/BMK1 Is Indispensable for Optimal Colony-Stimulating Factor 1 (CSF-1)-Induced Proliferation in Macrophages in a Src-Dependent Fashion

“…CSF-1R also recruits Src family kinases (SFK) 3 via an autophosphorylation site in the juxtamembrane domain (3)(4)(5). It has been recently demonstrated that PI3K and ERK1/2, but not STAT-3, are essential for optimal mitogenesis elicited by CSF-1 (6).…”