Abstract
Cyr61 is a member of the CCN family of growth factors; these proteins are secreted and can act as ligands of distinct integrins. We show that Cyr61 can enhance tumorigenicity of glioma cells acting through activated integrin-linked kinase (ILK) to stimulate beta-catenin-TCF/Lef and Akt signaling pathways. Overexpression of Cyr61 occurred in highly tumorigenic glioma cell lines and in 68% of the most malignant glioblastoma multiforme brain tumors. Forced expression of Cyr61 in U343 glioma cells accelerated their growth in liquid culture, enhanced their anchorage-independent proliferation in soft agar, and significantly increased their ability to form large, vascularized tumors in nude mice. Overexpression of Cyr61 in the U343 cells led to the up-regulation of distinct integrins, including beta1 and alphanubeta3, which have been shown to interact with Cyr61 and ILK. The activity of ILK was increased dramatically in these cells. Overexpression of Cyr61 also resulted in the phosphorylation of glycogen synthase kinase-3beta and accumulation and nuclear translocation of beta-catenin, leading to activation of the beta-catenin-TCF/Lef-1 signaling pathway. Furthermore, forced expression of Cyr61 in the glioma cells activated phosphatidylinositol 3'-kinase pathway, resulting in prominent phosphorylation of Akt and the antiapoptotic protein Bad. Cyr61 appears to stimulate several signaling pathways in the development of gliomas.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Carrier Proteins / metabolism
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Cell Cycle
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Cell Movement
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Cell Nucleus
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Colony-Forming Units Assay
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Cysteine-Rich Protein 61
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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DNA-Binding Proteins / metabolism*
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Glioma / metabolism*
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Glioma / pathology
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Glycogen Synthase Kinases / metabolism
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Humans
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Immediate-Early Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / metabolism*
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Lymphoid Enhancer-Binding Factor 1
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Mice
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Mice, Nude
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Neoplasms, Experimental / blood supply
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Signal Transduction*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Cells, Cultured
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bcl-Associated Death Protein
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beta Catenin
Substances
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BAD protein, human
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Bad protein, mouse
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CCN1 protein, human
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CCN1 protein, mouse
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Carrier Proteins
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Cysteine-Rich Protein 61
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Lymphoid Enhancer-Binding Factor 1
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factors
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bcl-Associated Death Protein
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beta Catenin
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integrin-linked kinase
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Protein-Tyrosine Kinases
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Glycogen Synthase Kinases
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt