Extracellular Membrane-proximal Domain of HAb18G/CD147 Binds to Metal Ion-dependent Adhesion Site (MIDAS) Motif of Integrin β1 to Modulate Malignant Properties of Hepatoma Cells

• Published in: The Journal of biological chemistry Vol. 287; no. 7; pp. 4759 - 4772
• Main Authors: Li, Yong, Wu, Jiao, Song, Fei, Tang, Juan, Wang, Shi-Jie, Yu, Xiao-Ling, Chen, Zhi-Nan, Jiang, Jian-Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Motifs; Animals; Basigin - genetics; Basigin - metabolism; Binding Site; Cancer Biology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CD147; Cell Adhesion; Cell Biology; Cell Movement; Cell-Cell Interaction; Collagenases; Disease Models, Animal; Focal Adhesion Kinase; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Hepatocellular Carcinoma; Humans; Integrin; Integrin beta1 - genetics; Integrin beta1 - metabolism; Ions - metabolism; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Metal Ion-dependent Adhesion Site; Metals - metabolism; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Transplantation; PI 3-Kinase (PI3K); Protein Structure, Tertiary; Signal Transduction; Transplantation, Heterologous; Metal Ion-dependent Adhesion Site; Integrin; Cell-Cell Interaction; PI 3-Kinase (PI3K); Binding Site; Cancer Biology; Focal Adhesion Kinase; CD147; Hepatocellular Carcinoma
• ISSN: 0021-9258; 1083-351X; 1067-8816; 1083-351X
• DOI: 10.1074/jbc.M111.277699

Several lines of evidence suggest that HAb18G/CD147 interacts with the integrin variants α3β1 and α6β1. However, the mechanism of the interaction remains largely unknown. In this study, mammalian protein-protein interaction trap (MAPPIT), a mammalian two-hybrid method, was used to study the CD147-integrin β1 subunit interaction. CD147 in human hepatocellular carcinoma (HCC) cells was interfered with by small hairpin RNA. Nude mouse xenograft model and metastatic model of HCC were used to detect the role of CD147 in carcinogenesis and metastasis. We found that the extracellular membrane-proximal domain of HAb18G/CD147 (I-type domain) binds at the metal ion-dependent adhesion site in the βA domain of the integrin β1 subunit, and Asp179 in the I-type domain of HAb18G/CD147 plays an important role in the interaction. The levels of the proteins that act downstream of integrin, including focal adhesion kinase (FAK) and phospho-FAK, were decreased, and the cytoskeletal structures of HCC cells were rearranged bearing the HAb18G/CD147 deletion. Simultaneously, the migration and invasion capacities, secretion of matrix metalloproteinases, colony formation rate in vitro, and tumor growth and metastatic potential in vivo were decreased. These results indicate that the interaction of HAb18G/CD147 extracellular I-type domain with the integrin β1 metal ion-dependent adhesion site motif activates the downstream FAK signaling pathway, subsequently enhancing the malignant properties of HCC cells. Background: HAb18G/CD147 interacts with integrin β1 subunit. Results: Extracellular membrane-proximal domain of HAb18G/CD147 (I-type domain) binds at the metal ion-dependent adhesion site (MIDAS) in the βA domain of the integrin β1 subunit. Conclusion: Interaction of HAb18G/CD147 with integrin β1 activates the downstream FAK signaling pathway, enhancing the malignant properties of hepatocellular carcinoma cells. Significance: This is first time binding sites of CD147 and integrin β1 are revealed.