The phosphorylation of CD147 by Fyn plays a critical role for melanoma cells growth and metastasis

• Published in: Oncogene Vol. 39; no. 21; pp. 4183 - 4197
• Main Authors: Zhang, Xu, Huang, Zunnan, Guo, Yeye, Xiao, Ta, Tang, Ling, Zhao, Shuang, Wu, Lisha, Su, Juan, Zeng, Weiqi, Huang, Hongbin, Li, Zheng, Tao, Juan, Zhou, Jianda, Chen, Xiang, Peng, Cong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.05.2020; Nature Publishing Group
• Subjects: 13/105; 13/31; 13/51; 13/89; 14/5; 14/63; 38/111; 38/90; 42/109; 42/70; 631/154/555; 631/67/1813/1634; Amino Acid Substitution; Amodiaquine; Antibodies; Apoptosis; Basigin - genetics; Basigin - metabolism; CD147 antigen; Cell adhesion & migration; Cell Biology; Cell Line, Tumor; Extracellular matrix; Fyn protein; Gelatinase B; Glycosylation; Growth; Human Genetics; Humans; Internal Medicine; Kinases; Leukocyte migration; Lymphocytes T; Matrix metalloproteinase; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Medicine; Medicine & Public Health; Melanoma; Melanoma - genetics; Melanoma - pathology; Metalloproteinase; Metastases; Metastasis; Mutation, Missense; Neoplasm Metastasis; Oncology; Phenotypes; Phosphorylation; Phosphorylation - genetics; Proto-Oncogene Proteins c-fyn - genetics; Proto-Oncogene Proteins c-fyn - metabolism; Signal Transduction; T cell receptors; T cells; Tumor cells; Tyrosine; Viral antibodies; Denmark; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1287-3

CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a transmembrane glycoprotein that is highly expressed in tumor cells, particularly melanoma cells, and plays critical roles in tumor cell metastasis through the regulation of matrix metalloprotease (MMP) expression. In this study, we identified Fyn as a novel interacting protein of CD147. Fyn is a member of the Src family of nonreceptor tyrosine kinases that regulates diverse physiological processes, such as T lymphocyte differentiation, through the TCR signaling pathway. Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Two phosphospecific antibodies against Y140 and Y183 were developed to validate the phosphorylation of CD147 by Fyn. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. In addition, CD147-FF significantly blocked MMP-9 expression as well as cell migration. Moreover, we found that Fyn is overexpressed in clinical melanoma tissues as well as in melanoma cell lines. Knockdown of Fyn expression markedly attenuated the malignant phenotype of melanoma cells in vitro and in vivo through downregulation of CD147 phosphorylation, indicating that Fyn/CD147 is a potential target molecule in melanoma treatment. Finally, through virtual screening, we identified amodiaquine as a potential inhibitor targeting the Fyn/CD147 axis. Amodiaquine treatment dramatically inhibited the phosphorylation of CD147 by Fyn, thus attenuating melanoma cell growth and invasion in vitro and in vivo, suggesting that amodiaquine is a promising inhibitor for melanoma treatment.