Hepatocyte growth factor induces delayed STAT3 phosphorylation through interleukin-6 expression |
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| Authors: | Bok-Soon Lee Minseon Park Hyun-Young Cha Jae-Ho Lee |
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| Affiliation: | 1. Laboratory of Medical Investigation in Dermatology and Immunodeficiences-LIM 56, Department of Dermatology, Faculty of Medicine, University of Sao Paulo, Avenida Dr Eneas de Carvalho Aguiar, 470 – Prédio 2–3° andar, 05403-000 Cerqueira César, Sao Paulo, Brazil;2. Department of Dermatology, Faculty of Medicine, University of Sao Paulo, Avenida Dr. Eneas de Carvalho Aguiar 500, 05403-000 Cerqueira Cesar, Sao Paulo, Brazil;3. Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Avenida Prof. Lineu Prestes 1730, 05508-000 Cidade Universitaria, Sao Paulo, Brazil;1. Center for Interdisciplinary Research, Tohoku University, Sendai 980-8578, Japan;2. Department of Project Programs, Tohoku University, Sendai 980-8575, Japan;3. Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan;4. International Advanced Research and Education Organization, Tohoku University, Sendai 980-8578, Japan;5. Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan;1. Department of Biochemistry and Molecular Biology, 1011 NW 15th Street, Gautier Building, Room 528, University of Miami School of Medicine, Miami, FL 33136-1019, USA;2. Diabetes Research Institute, 1450 NW 10th Ave, University of Miami School of Medicine, Miami, FL 33136-1011, USA |
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| Abstract: | Met receptor tyrosine kinase mediates pleiotropic cellular responses following its activation by hepatocyte growth factor or scatter factor (HGF/SF). STAT3 was reported to be one of direct downstream molecules in HGF/SF-Met signaling. In the present study, however, we observed that Tyr705 of STAT3 was phosphorylated from 2 h or 6 h in NIH3T3 and Chang liver cells, respectively, after HGF/SF treatment. Blocking of the phosphorylation by cycloheximide or actinomycin D and the rapid STAT3 phosphorylation with the conditioned medium from HGF/SF-treated NIH3T3 cells suggested that a newly synthesized secretory protein was responsible for the delayed STAT3 phosphorylation. Among the known mediators to induce STAT3 phosphorylation, interleukin-6 (IL-6) mRNA and protein were induced by HGF/SF, and the released IL-6 was accumulated in the conditioned medium after HGF/SF treatment. Furthermore, the neutralizing IL-6 antibody abolished the STAT3 phosphorylation. Treatment with LY294002, a PI3 kinase inhibitor, but not with other signal inhibitors, resulted in the loss of delayed STAT3 phosphorylation by HGF/SF, showing the involvement of PI3 kinase pathway. Collectively, these results demonstrate that HGF/SF-Met signal cascade stimulates IL-6 production via PI3 kinase pathway, leading to STAT3 phosphorylation as a secondary effect. |
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