Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway.
Leptin is an adipocyte-secreted hormone that centrally regulates weight control. However, the leptin receptor is expressed not only in the central nervous system, but also in other systems, such as reproductive, hematopoietic, and immune tissues, suggesting various roles in addition to the regulation of food intake and energy expenditure. The leptin receptor bears homology to members of the class I cytokine receptor family. Leptin has previously been shown to enhance cytokine production by murine peritoneal macrophages and human circulating monocytes, where human leptin promotes activation and proliferation. We have recently found that the leptin receptor is expressed not only in monocytes but also in both CD4(+) and CD8(+) T lymphocytes. Besides, leptin enhances proliferation and activation of T lymphocytes when they are costimulated by PHA or Con A. In this paper, we have studied the signal transduction of the leptin receptor in peripheral blood mononuclear cells. We found that leptin stimulation activates the JAK-STAT signaling pathway. More specifically, we found that JAK-2/3 and STAT-3 are activated by tyrosine phosphorylation upon leptin stimulation. Moreover, leptin stimulated tyrosine phosphorylation of the RNA binding protein Sam68 and its association with STAT-3. These effects were dose-dependent (0.1-10 nM) and transient (5-30 min). We also observed the leptin stimulated translocation of activated STAT-3 from the cytoplasm to the nucleus. These results indicate that human leptin receptor in circulating mononuclear cells has the signaling capacity to activate JAK-STAT cascade. This pathway may mediate, at least in part, the action of human leptin in human peripheral blood mononuclear cells.
Sanchez-Margalet
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Department of Medical Biochemistry and Molecular Biology, School of Medicine, Investigation Unit, University of Seville, 41009-Seville, Spain. vsanchez@cica.es
Martin-Romero
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C
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D001769:Blood / Q000276:immunology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D020738:Leptin / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; D020738:Leptin; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053614:Janus Kinase 2; D053616:Janus Kinase 3