MUC20 Suppresses the Hepatocyte Growth Factor-Induced Grb2-Ras Pathway by Binding to a Multifunctional Docking Site of Met

Abstract

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.

We thank T. Chuman, K. Iwata, H. Sasai, H. Ogasawara, and M. Sasabuchi (JT Pharma); E. Imai (Osaka University); W. Munger (Gene Logic Inc.); and R. Falk, C. Jennette, and D. Alcorta (University of North Carolina) for discussion and H. Murakoshi, I. Suganuma, K. Ishii, M. Saito, S. Kubo, Y. Mohara, and N. Ookawara (JTCS) for technical assistance. We also thank J. Miyazaki (Osaka University) for the vector pCAGGS.