title: A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism.
abstract: Met is the transmembrane tyrosine kinase cell surface receptor for hepatocyte growth factor (HGF) and is structurally related to the insulin receptor (INSR) tyrosine kinase. Here we report that the HGF-Met axis regulates metabolism by stimulating hepatic glucose uptake and suppressing hepatic glucose output. We show that Met is essential for an optimal hepatic insulin response by directly engaging INSR to form a Met-INSR hybrid complex, which culminates in a robust signal output. We also found that the HGF-Met system restores insulin responsiveness in a mouse model of insulin refractoriness. These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Arlee
authors.initials: A
authors.lastname: Fafalios
authors.forename: Jihong
authors.initials: J
authors.lastname: Ma
authors.forename: Xinping
authors.initials: X
authors.lastname: Tan
authors.forename: John
authors.initials: J
authors.lastname: Stoops
authors.forename: Jianhua
authors.initials: J
authors.lastname: Luo
authors.forename: Marie C
authors.initials: MC
authors.lastname: Defrances
authors.forename: Reza
authors.initials: R
authors.lastname: Zarnegar
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy; D015536:Down-Regulation; D005260:Female; D005947:Glucose / Q000378:metabolism*; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020239:Receptor Cross-Talk; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D034741:RNA, Small Interfering; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D011972:Receptor, Insulin; D005947:Glucose
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