Dimerization is essential for HAb18G/CD147 promoting tumor invasion via MAPK pathway

• Published in: Biochemical and biophysical research communications Vol. 419; no. 3; pp. 517 - 522
• Main Authors: Cui, Hong-Yong, Guo, Tao, Wang, Shi-Jie, Zhao, Pu, Dong, Zhi-Shou, Zhang, Yang, Jiang, Jian-Li, Chen, Zhi-Nan, Yu, Xiao-Ling
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.03.2012
• Subjects: Basigin - genetics; Basigin - metabolism; CD147; Cell Line, Tumor; crystal structure; Dimerization; glycoproteins; Humans; immunoglobulins; Matrix metalloproteinase 2; Matrix Metalloproteinase 2 - metabolism; metastasis; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase Kinases - metabolism; mutants; Mutation; neoplasm cells; Neoplasm Invasiveness; neoplasms; Protein Multimerization; Neoplasm invasiveness; Matrix metalloproteinase 2; CD147; Dimerization
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2012.02.049

► HAb18G/CD147 forms dimers both in solution and in living cells. ► Dimerization of HAb18G/CD147 can be disrupted by mutagenesis. ► Key residues for dimerization of HAb18G/CD147 were identified. ► Disruption of HAb18G/CD147 dimerization attenuates the MAPK activation in tumor. ► Dimerization is required for HAb18G/CD147 induced MMP2 expression and tumor invasion. HAb18G/CD147 is a transmembrane glycoprotein of the immunoglobulin superfamily (IgSF) and is reported to be correlated with invasion and metastasis of many cancers. The crystal structure of HAb18G/CD147 ectodomain has shown that it can form homodimers in crystal. However, the functional significance of HAb18G/CD147 dimerization remains unclear. In the present study, guided by the crystal structure, we performed extensive mutational and functional studies to identify residues critical for dimerization and molecular function of HAb18G/CD147. Fourteen mutants were purified and evaluated for their ability to form dimers in solution and in living cells. Subsequent functional validation revealed that K63E and S193A mutants, which disrupted CD147 dimerization both in solution and in living cells, showed clearly dominant-negative effects on MAPK activation, MMP2 induction and invasiveness in tumor cells. Taken together, the present study provides mutational and functional evidences demonstrating for the first time the functional importance of CD147 dimerization and its direct correlation with invasion and metastasis of tumor cells.