Phosphorylation of GATA2 by Akt Increases Adipose Tissue Differentiation and Reduces Adipose Tissue-Related Inflammation: A Novel Pathway Linking Obesity to Atherosclerosis

Department of Internal Medicine, University of Rome Tor Vergata, Policlinico Tor Vergata-PTV University Hospital, Rome, Italy.
Circulation (Impact Factor: 14.43). 05/2005; 111(15):1946-53. DOI: 10.1161/01.CIR.0000161814.02942.B2
Source: PubMed


Obesity-related inflammation is emerging as a major cause of insulin resistance and cardiovascular diseases. GATA2 transcription factor is an inhibitor of adipogenesis and an activator of vascular cells. We hypothesized that GATA2 activity is controlled by insulin during adipogenesis, linking metabolic homeostasis and inflammation.
We show that insulin induces GATA2 phosphorylation on serine 401 in a PI-3K/Akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs GATA2 translocation to the nucleus and its DNA binding activity. A GATA2 mutant not phosphorylable by Akt (GATA2(S401A)) acts similarly to wild-type GATA2. In contrast, a GATA2 mutant that mimics Akt phosphorylation (GATA2(S401D)) is restrained in the cytoplasm. Cultured preadipocytes bearing GATA2(S401A) do not convert to adipocytes and express high levels of inflammatory cytokines like monocyte chemotactic protein-1 (MCP-1). On the contrary, GATA2(S401D) preadipocytes differentiate to adipocytes. When GATA2(S401A) preadipocytes are injected in mice fed a high-fat diet, they do not differentiate adequately into adipocytes, maintaining the expression of inflammatory markers like MCP-1. In contrast, injection of GATA2(S401D) preadipocytes in mice fed a high-fat diet results in development of adipocytes and no expression of inflammatory markers.
GATA2 could be a new target in the prevention and treatment of obesity-related inflammation and its complications.

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    • "Akt-induced phosphorylation of FKHR and FKHRL1 promoted their cytosolic retention, eventually sequestering them away from their nuclear targets. Akt also inhibited the function of transcription factor GATA2 through similar mechanism [33]. These findings suggested that an activated Akt could contribute to malignant growth and transformation by modulating the function of key transcription factors involved in cellular differentiation and growth. "
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    ABSTRACT: The nuclear receptor co-repressor (N-CoR) is a key component of the generic co-repressor complex that plays an important role in the control of cellular growth and differentiation. As shown by us recently, the growth suppressive function of N-CoR largely relies on its capacity to repress Flt3, a key regulator of cellular gorwth during normal and malignant hematopoesis. We further demonstrated how de-repression of Flt3 due to the misfolded conformation dependent loss (MCDL) of N-CoR contributed to malignant growth in acute myeloid leukemia (AML). However, the molecular mechanism underlying the MCDL of N-CoR and its implication in AML pathogenesis is not fully understood. Here, we report that Akt-induced phosphorylation of N-CoR at the consensus Akt motif is crucial for its misfolding and subsequent loss in AML (AML-M5). N-CoR displayed significantly higher level of serine specific phosphorylation in almost all AML-M5 derived cells and was subjected to processing by AML-M5 specific aberrant protease activity. To identify the kinase linked to N-CoR phosphorylation, a library of activated kinases was screened with the extracts of AML cells; leading to the identification of Akt as the putative kinase linked to N-CoR phosphorylation. Consistent with this finding, a constitutively active Akt consistently phosphorylated N-CoR leading to its misfolding; while the therapeutic and genetic ablation of Akt largely abrogated the MCDL of N-CoR in AML-M5 cells. Site directed mutagenic analysis of N-CoR identified serine 1450 as the crucial residue whose phosphorylation by Akt was essential for the misfolding and loss of N-CoR protein. Moreover, Akt-induced phosphorylation of N-CoR contributed to the de-repression of Flt3, suggesting a cross talk between Akt signaling and N-CoR misfolding pathway in the pathogenesis of AML-M5. The N-CoR misfolding pathway could be the common downstream thread of pleiotropic Akt signaling activated by various oncogenic insults in some subtypes of leukemia and solid tumors.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "is not a critical signaling component down - stream of insulin for proper upregulation of the adipogenic factors and the induction of adipogenesis . Under these conditions , other branches of Akt signaling , such as forkhead protein 1 ( FOXO1 ; Nakae et al . , 2003 ) , hepatocyte nuclear factors ( Foxa ; Wolfrum et al . , 2003 ) and GATA factors ( Menghini et al . , 2005 ) are play - ing roles in promoting adipogenesis ( Rosen and MacDougald , 2006 ) . Therefore , the Akt branches related to insulin signaling play complementary and , perhaps , partially redundant roles in driving adipocyte differentiation . Despite the observed functional differences between ghrelin and insulin system under ␤ - arrestin"
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    ABSTRACT: β-Arrestins were identified as scaffold-proteins that have the capacity to desensitize G protein-coupled receptors. However, it has been found that β-arrestins activate signaling pathways independent of G protein activation. The diversity of these signaling pathways has also been recognized for receptor tyrosine kinase. The aim of the present study was to validate the β-arrestin-dependent signaling mechanism(s) responsible for regulation of adipogenesis. Two signal models were selected, ghrelin and insulin, based on its β-arrestin-associated Akt activity. Herein, we found that β-arrestin 1 and 2 were essential molecules for adipocyte differentiation. More specifically, the role of these scaffolding proteins was demonstrated by depletion of β-arrestin 1 and 2 during ghrelin-induced adipogenesis in 3T3-L1 cells, which decreased the adipocyte differentiation and the expression levels of master regulators of early, the CCAAT/enhancer-binding protein β (C/EBPβ) and the CCAAT/enhancer-binding protein δ (C/EBPδ), and terminal, the peroxisome proliferator-activated receptor (PPARγ) and the CCAAT/enhancer-binding protein α (C/EBPα), adipogenesis. Accordingly ghrelin-induced Akt activity and its downstream targets, the mammalian target of rapamycin complex 1 (mTORC1) and the ribosomal protein S6 kinase beta-1 (S6K1), were inhibited by β-arrestin 1 and 2 siRNAs. By contrast, assays performed during insulin-activated adipogenesis showed an intensifying effect on the adipocyte differentiation as well as on the expression of C/EBPβ, C/EBPδ, PPARγ and C/EBPα⋅ The increase in insulin-induced adipogenesis by β-arrestin knock-down was concomitant to a decrease in the insulin receptor susbtrate-1 (IRS-1) serine phosphorylation, proving the loss of the negative feedback loop on IRS-1/phosphoinositide 3-kinase (PI3K)/Akt. Therefore, β-arrestins control the extent and intensity of the lipogenic and adipogenic factors associated to Akt signaling, although the mechanistic and functional principles that underlie the connection between signaling and β-arrestins are specifically associated to each receptor type.
    Full-text · Article · Apr 2013 · The international journal of biochemistry & cell biology
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    • "Insulin treatment of HEK293 cells stimulates PI3-K/Akt signaling, which induces GATA-2 phosphorylation at serine 401 (105). Serine 401 phosphorylation was reported to impair nuclear translocation, based on overexpression of the mutant in HEK293 cells (105). In addition, naked DNA-binding studies suggested that serine 401 phosphorylation impairs GATA-2 DNA-binding activity (105). "
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    ABSTRACT: Numerous examples exist of how disrupting the actions of physiological regulators of blood cell development yields hematologic malignancies. The master regulator of hematopoietic stem/progenitor cells GATA-2 was cloned almost 20 years ago, and elegant genetic analyses demonstrated its essential function to promote hematopoiesis. While certain GATA-2 target genes are implicated in leukemogenesis, only recently have definitive insights emerged linking GATA-2 to human hematologic pathophysiologies. These pathophysiologies include myelodysplastic syndrome, acute myeloid leukemia and an immunodeficiency syndrome with complex phenotypes including leukemia. As GATA-2 has a pivotal role in the etiology of human cancer, it is instructive to consider mechanisms underlying normal GATA factor function/regulation and how dissecting such mechanisms may reveal unique opportunities for thwarting GATA-2-dependent processes in a therapeutic context. This article highlights GATA factor mechanistic principles, with a heavy emphasis on GATA-1 and GATA-2 functions in the hematopoietic system, and new links between GATA-2 dysregulation and human pathophysiologies.
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