Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells.
The biological significance of a known normal and cancer stem cell marker CD133 remains elusive. We now demonstrate that the phosphorylation of tyrosine-828 residue in CD133 C-terminal cytoplasmic domain mediates direct interaction between CD133 and phosphoinositide 3-kinase (PI3K) 85 kDa regulatory subunit (p85), resulting in preferential activation of PI3K/protein kinase ... B (Akt) pathway in glioma stem cell (GSC) relative to matched nonstem cell. CD133 knockdown potently inhibits the activity of PI3K/Akt pathway with an accompanying reduction in the self-renewal and tumorigenicity of GSC. The inhibitory effects of CD133 knockdown could be completely rescued by expression of WT CD133, but not its p85-binding deficient Y828F mutant. Analysis of glioma samples reveals that CD133 Y828 phosphorylation level is correlated with histopathological grade and overlaps with Akt activation. Our results identify the CD133/PI3K/Akt signaling axis, exploring the fundamental role of CD133 in glioma stem cell behavior.
Mesh Terms:
AC133 Antigen, Animals, Antigens, CD, Blotting, Western, Cell Transformation, Neoplastic, Class Ia Phosphatidylinositol 3-Kinase, Glioma, Glycoproteins, Humans, Immunoprecipitation, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Missense, Neoplastic Stem Cells, Peptides, Phosphorylation, Proto-Oncogene Proteins c-akt, Signal Transduction
AC133 Antigen, Animals, Antigens, CD, Blotting, Western, Cell Transformation, Neoplastic, Class Ia Phosphatidylinositol 3-Kinase, Glioma, Glycoproteins, Humans, Immunoprecipitation, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Missense, Neoplastic Stem Cells, Peptides, Phosphorylation, Proto-Oncogene Proteins c-akt, Signal Transduction
Proc. Natl. Acad. Sci. U.S.A.
Date: Apr. 23, 2013
PubMed ID: 23569237
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