MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met.
A cDNA encoding a novel mucin protein, MUC20, was isolated as a gene that is up-regulated in the renal tissues of patients with immunoglobulin A nephropathy. We demonstrate here that the C terminus of MUC20 associates with the multifunctional docking site of Met without ligand activation, preventing Grb2 recruitment to Met and thus attenuating hepatocyte growth factor (HGF)-induced transient extracellular signal-regulated kinase-1 and -2 activation. Production of MUC20 reduced HGF-induced matrix metalloproteinase expression and proliferation, which require the Grb2-Ras pathway, whereas cell scattering, branching morphogenesis, and survival via the Gab1/phosphatidylinositol 3-kinase (PI3K) pathways was not affected. Thus, MUC20 reduces HGF-induced activation of the Grb2-Ras pathway but not the Gab1/PI3K pathways. We further demonstrate that the cytoplasmic domain of MUC20 has the ability to oligomerize and that the oligomerization augments its affinity for Met. Taken together, these results suggest that MUC20 is a novel regulator of the Met signaling cascade which has a role in suppression of the Grb2-Ras pathway.
Central Pharmaceutical Research Institute, Pharmaceutical Frontier Research Laboratories, Japan Tobacco Inc., Yokohama, 236-0004, Japan.
Toshio
T
Higuchi
Takuya
T
Orita
Ken
K
Katsuya
Yoshiki
Y
Yamasaki
Kiyotaka
K
Akiyama
Huiping
H
Li
Tadashi
T
Yamamoto
Yutaka
Y
Saito
Motonao
M
Nakamura
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D051380:GRB2 Adaptor Protein; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C490897:Gab1 protein, mouse; C495949:Grb2 protein, mouse; C490965:MUC20 protein, human; C490962:Muc20 protein, mouse; D009077:Mucins; D010750:Phosphoproteins; D011506:Proteins; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins