CD133 activates PI3K/AKT and enhances GSC self-renewal and tumorigenicity via binding to p85.

  • Major finding: CD133 activates PI3K/AKT and enhances GSC self-renewal and tumorigenicity via binding to p85.

  • Mechanism: Phosphorylation of CD133 at Y828 is required for interaction with p85 and stimulation of AKT.

  • Impact: Phosphorylated CD133 correlates with higher glioma grade and is a functional marker of GSCs.

CD133 (also known as prominin 1) is a transmembrane glycoprotein commonly used as a cell-surface marker to isolate cancer stem cells (CSC) in several types of human tumors. CD133-positive tumor cells have been shown to have elevated AKT activity, which promotes CSC survival and self-renewal and may confer chemoresistance. However, the functional role of CD133 and the mechanisms by which the phosphoinositide 3-kinase (PI3K)/AKT pathway is activated in CSCs are unknown. Wei and colleagues isolated CD133-positive tumor cells from human glioblastoma samples and found that these highly tumorigenic glioma stem cells (GSC) exhibited enhanced PI3K activity and increased AKT phosphorylation compared with matched CD133-negative glioma cells. The preferential upregulation of PI3K/AKT signaling was dependent on the expression of CD133, which directly bound to the p85 PI3K regulatory subunit in CD133-expressing glioma cells and human glioblastoma tissues and triggered p85 recruitment to the plasma membrane. Interaction of p85 with CD133 was specifically mediated by SRC-driven phosphorylation of the CD133 C-terminal cytoplasmic domain at tyrosine 828 (Y828) within a conserved sequence containing a nonconsensus p85-binding motif. Mutation of Y828 to phenylalanine (Y828F) abolished CD133 binding to p85 and prevented rescue of AKT phosphorylation in CD133-depleted glioma cells. Knockdown of CD133 diminished the self-renewal and tumor-initiating potential of GSC, suggesting that CD133-stimulated PI3K/AKT signaling may be required for GSC behavior. Consistent with this idea, expression of wild-type but not Y828F mutant CD133 restored GSC self-renewal and tumorigenicity. Moreover, elevated CD133 Y828 phosphorylation correlated with high tumor grade and was associated with AKT activation in human glioblastoma samples. These results identify CD133 as an important regulator of PI3K activity in GSCs and as a functional marker of glioma-initiating cells.

Wei Y, Jiang Y, Zou F, Liu Y, Wang S, Xu N, et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells. Proc Natl Acad Sci USA 2013 Apr 8 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013