Liu Chanjuan, Li Yinan, Xing Yang, Cao Benjin, Yang Fan, Yang Tianxiao, Ai Zhilong, Wei Yuanyan, Jiang Jianhai
From the Key Laboratory of Glycoconjugates Research, Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai 200032, China and.
Division of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
J Biol Chem. 2016 Jul 22;291(30):15540-50. doi: 10.1074/jbc.M115.712976. Epub 2016 May 24.
CD133, a widely known cancer stem cell marker, has been proved to promote tumor metastasis. However, the mechanism by which CD133 regulates metastasis remains largely unknown. Here, we report that CD133 knockdown inhibits cancer cell migration, and CD133 overexpression promotes cell migration. CD133 expression is beneficial to activate the Src-focal adhesion kinase (FAK) signaling pathway. Further studies show that CD133 could interact with Src, and the region between amino acids 845 and 857 in the CD133 C-terminal domain is indispensable for its interaction with Src. The interaction activates Src to phosphorylate its substrate FAK and to promote cell migration. Likewise, a Src binding-deficient CD133 mutant loses the abilities to increase Src and FAK phosphorylation and to promote cell migration. Inhibition of Src activity by PP2, a known Src activity inhibitor, could block the activation of FAK phosphorylation and cell migration induced by CD133. In summary, our data suggest that activation of FAK by the interaction between CD133 and Src promotes cell migration, providing clues to understand the migratory mechanism of CD133(+) tumor cells.
CD133是一种广为人知的癌症干细胞标志物，已被证明可促进肿瘤转移。然而，CD133调节转移的机制在很大程度上仍不清楚。在此，我们报告CD133基因敲低会抑制癌细胞迁移，而CD133过表达则会促进细胞迁移。CD133的表达有利于激活Src-黏着斑激酶（FAK）信号通路。进一步研究表明，CD133可与Src相互作用，且CD133 C末端结构域中第845至857位氨基酸之间的区域对于其与Src的相互作用必不可少。这种相互作用激活Src使其底物FAK磷酸化并促进细胞迁移。同样，一种缺乏Src结合能力的CD133突变体失去了增加Src和FAK磷酸化以及促进细胞迁移的能力。已知的Src活性抑制剂PP2对Src活性的抑制可阻断CD133诱导的FAK磷酸化激活和细胞迁移。总之，我们的数据表明，CD133与Src之间的相互作用激活FAK从而促进细胞迁移，为理解CD133(+)肿瘤细胞的迁移机制提供了线索。
