title: Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes.
abstract: Met/hepatocyte growth factor (HGF) receptor plays a definitive role in hepatocyte proliferation and liver regeneration. Phosphorylation of Ser985 in Met (Met-Ser985) down regulate tyrosine phosphorylation and activation of Met. However, mechanism of Met inactivation by Met-Ser985 phosphorylation and its biological significance on hepatocyte proliferation and liver regeneration are not well known. Here, we investigated biological role of Met-Ser985 phosphorylation in hepatocytes and liver. In primary cultured hepatocytes, HGF-dependent Met activation and mitogenesis were suppressed when Met-Ser985 was phosphorylated. Cell surface Met was decreased upon Met-Ser985 phosphorylation through endocytosis, suggesting a mechanism by which Met activation could be suppressed. In mice, HGF induced proliferation of hepatocyte in injured livers, but not in non-injured livers. Met-Ser985 phosphorylation was decreased after liver injury and associated with Met tyrosine phosphorylation/activation during liver regeneration. These results indicate that Met activation is regulated reciprocally to Met-Ser985 phosphorylation in the primary cultured hepatocytes and the liver following injury. Our study suggests that the phosphorylation of Met-Ser985 in hepatocytes plays a regulatory role in Met activation in response to quiescence, injury, and regeneration.
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Nakayama
authors.forename: Katsuya
authors.initials: K
authors.lastname: Sakai
authors.forename: Atsuko
authors.initials: A
authors.lastname: Yamashita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008934:Mitogens / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D008934:Mitogens; D010768:Phosphoserine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met