Regulation of Jak Kinases by Intracellular Leptin Receptor Sequences

Kloek, Carolyn E.; Haq, Asma K.; Dunn, Sarah L.; Lavery, Hugh J.; Banks, Alexander S.; Myers, Martin G.

doi:10.1074/jbc.m205148200

Cited by 203 publications

(163 citation statements)

References 33 publications

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“…Recent data indicate that Jak2 represents the unique Jak kinase involved in signaling by the intracellular domain of Ob-Rb (44). In this regard, however, the relationship of leptin to key mitogenic and anti-apoptotic signaling systems, including Erk and Akt, has only recently been examined, and not in HSCs.…”

Section: Discussionmentioning

confidence: 99%

Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation

et al. 2004

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A key feature in the molecular pathogenesis of liver fibrosis requires maintenance of the activated hepatic stellate cell (HSC) phenotype by both proliferation and inhibition of apoptosis. We provide evidence that leptin is a potent HSC mitogen and dramatically inhibits stellate cell apoptosis. Leptin proved to be as potent an HSC mitogen as platelet-derived growth factor (PDGF) as assessed by bromodeoxyuridine (BrdU) incorporation in isolated primary HSCs; data using fluorescent propidium iodide (PI) uptake revealed that leptin, like PDGF, increased HSC populations in the S-and G 2 /M-phases of the cell cycle. Leptin resulted in a robust increase in cyclin D1 expression. Using the chemical inhibitor of Janus kinase 2 (Jak2) activity, AG 490, and overexpression of the suppressor of cytokine signaling 3 (SOCS-3), we show that blockade of leptin receptor (Ob-Rb) phosphorylation blocks leptin-induced HSC proliferation. Leptinassociated phosphorylation of both extracellular regulated kinase (p44/p42, Erk) and Akt is also prohibited. Further, the PI-3 kinase inhibitor LY294002 and MAPK inhibitor PD98059 were found to significantly reduce leptin-induced HSC proliferation, thereby indicating that leptin induced HSC proliferation is Akt-and Erk-dependent. Akt was also protective against HSC apoptosis. Leptin abolished both cycloheximide-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, demonstrated by reduced caspase-3 activity, HSC-TUNEL staining, and DNA fragmentation. We conclude that leptin acts as a direct hepatic stellate cell survival agonist. Importantly, we have demonstrated that leptin-induced HSC proliferation and survival by Ob-Rb phosphorylation are both Erk-and Akt-dependent. Keywords nonalcoholic steohepatitis (NASH); liver fibrosis; proliferation; MAP kinase; PI-3 kinaseThe role of leptin, a 16 kDa protein hormone, in liver disease may be distinctly important as human obesity and diabetes mellitus type II become more prevalent (1). Nonalcoholic steatohepatitis (NASH) is characterized by fatty change of the liver with various degrees of inflammation and fibrosis (2,3). The exact mechanism by which leptin promotes liver fibrosis is unknown. Recently, a role for leptin in the molecular pathogenesis of mammalian fibrosis has been substantiated in glomerulosclerosis (4) as well as in liver fibrosis (5)(6)(7)(8) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript peripheral tissues, leptin exerts control on body weight homeostasis via inhibitory actions on glucose metabolism and insulin secretion (9). Ob-Rb is the functional form of the membrane-associated leptin receptor. It is related to the class II cytokine group receptors binding interleukin-2, interferon, and growth hormone and is closely related to the gp130 signal-transducing component of the interleukin-6 and the G-CSF receptor (10,11). The long form of the leptin receptor, Ob-Rb, is present in various peripheral organs, including inflammatory blood cells, lung, kidney, liver,...

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Section: Discussionmentioning

confidence: 99%

Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation

et al. 2004

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“…Leptin binding to LRb initiates intracellular signaling by activating the LRb-associated Jak2 (Janus kinase 2) tyrosine kinase, resulting in Jak2 autophosphorylation and the phosphorylation of intracellular tyrosine residues on LRb (Bjorbaek et al, 1997;White et al, 1997;Banks et al, 2000;Kloek et al, 2002). Phosphorylated Tyr 1138 of LRb recruits the latent transcription factor STAT3 (signal transducer and activator of transcription 3), resulting in its phosphorylation and activation to mediate the transcription of POMC and other genes (Vaisse et al, 1996;White et al, 1997;Banks et al, 2000;Bates et al, 2003;Munzberg et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Münzberg¹,

Jobst²,

Bates³

et al. 2007

J. Neurosci.

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Leptin directly suppresses the activity of orexigenic neurons in the hypothalamic arcuate nucleus (ARC). We examined c-Fos-like immunoreactivity (CFLIR) as a marker of ARC neuronal activity in db/db mice devoid of the signaling form of the leptin receptor (LRb) and s/s mice that express LRb S1138 [which is defective for STAT3 (signal transducer and activator of transcription) signaling]. Both db/db and s/s animals are hyperphagic and obese. This analysis revealed that CFLIR in agouti related peptide-expressing orexigenic ARC neurons is basally elevated in db/db but not s/s mice. Consistent with these observations, electrophysiologic evaluation of a small number of neurons in s/s animals suggested that leptin appropriately suppresses the frequency of IPSCs on ARC proopiomelanocortin (POMC) neurons that are mediated by the release of GABA from orexigenic ARC neurons. CFLIR in POMC neurons of s/s mice was also increased compared with db/db animals. Thus, these data suggest that, although LRb3 STAT3 signaling is crucial for the regulation of feeding, it is not required for the acute or chronic regulation of orexigenic ARC neurons, and the activation of STAT3-mediated transcription by leptin is not required for the appropriate development of leptin responsiveness in these neurons.

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“…One form of the receptor, long form (OBRl), is highly expressed in the hypothalamus, and a short form (OBRs), is highly expressed in microvessels of the bloodbrain barrier (4,6). Upon binding to OBRl, leptin activates JAK2, which then initiates downstream signaling including members of the STAT family of transcription factors (7). The leptin receptor, through the activation of JAK2, is able to phosphorylate insulin receptor substrate (IRS) proteins and induce the IRS-PI3K signaling pathway (8,9).…”

mentioning

confidence: 99%

Leptin-Induced IL-6 Production Is Mediated by Leptin Receptor, Insulin Receptor Substrate-1, Phosphatidylinositol 3-Kinase, Akt, NF-κB, and p300 Pathway in Microglia

Tang

Lu²,

Yang

et al. 2007

The Journal of Immunology

145

112

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Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-6 production caused by leptin in microglia. Microglia expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-6 production. Leptin-mediated IL-6 production was attenuated by OBRl receptor antisense oligonucleotide, PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor (1L-6-hydroxymethyl-chiro-inositol-2-((R)-2-O-methyl-3-O-octadecylcarbonate)), NF-κB inhibitor (pyrrolidine dithiocarbamate), IκB protease inhibitor (l-1-tosylamido-2-phenylenylethyl chloromethyl ketone), IκBα phosphorylation inhibitor (Bay 117082), or NF-κB inhibitor peptide. Transfection with insulin receptor substrate (IRS)-1 small-interference RNA or the dominant-negative mutant of p85 and Akt also inhibited the potentiating action of leptin. Stimulation of microglia with leptin activated IκB kinase α/IκB kinase β, IκBα phosphorylation, IκBα degradation, p65 phosphorylation at Ser276, p65 and p50 translocation from the cytosol to the nucleus, and κB-luciferase activity. Leptin-mediated an increase of IκB kinase α/IκB kinase β activity, κB-luciferase activity, and p65 and p50 binding to the NF-κB element was inhibited by wortmannin, Akt inhibitor, and IRS-1 small-interference RNA. The binding of p65 and p50 to the NF-κB elements, as well as the recruitment of p300 and the enhancement of histone H3 and H4 acetylation on the IL-6 promoter was enhanced by leptin. Our results suggest that leptin increased IL-6 production in microglia via the leptin receptor/IRS-1/PI3K/Akt/NF-κB and p300 signaling pathway.

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Regulation of Jak Kinases by Intracellular Leptin Receptor Sequences

Cited by 203 publications

References 33 publications

Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation

Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation

Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Leptin-Induced IL-6 Production Is Mediated by Leptin Receptor, Insulin Receptor Substrate-1, Phosphatidylinositol 3-Kinase, Akt, NF-κB, and p300 Pathway in Microglia

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