Abstract
CCN family protein 2 (CCN2), also known as connective tissue growth factor, is a secreting protein that modulates multiple cellular events. We previously demonstrated the metastasis-suppressive effect of CCN2 in lung cancer cells. In this study, we investigate the role of CCN2 in anoikis, a form of programmed cell death that is critical in suppressing cancer metastasis. CCN2 binds to the epidermal growth factor receptor (EGFR) and triggers ubiquitination by inhibiting the formation of the β-pix/Cbl complex, resulting in the degradation of EGFR. Binding of CCN2 to EGFR suppresses the phosphorylation of c-Src and extracellular signal-regulated kinase but increases the expression of death-associated protein kinase, which leads to anoikis. Overall, our findings provide evidence validating the use of CCN2 as an anti-metastatic therapy in lung cancer patients, and prospect a potential therapeutic synergy between CCN2 and the anti-EGFR antibody for the treatment of lung cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Anoikis*
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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CSK Tyrosine-Protein Kinase
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Line, Tumor
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Cell Movement
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Connective Tissue Growth Factor / metabolism*
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Death-Associated Protein Kinases
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Guanine Nucleotide Exchange Factors / metabolism
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Humans
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Molecular Sequence Data
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Phosphorylation
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-cbl / metabolism
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Rho Guanine Nucleotide Exchange Factors
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Signal Transduction
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Ubiquitination
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src-Family Kinases / metabolism
Substances
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ARHGEF7 protein, human
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Apoptosis Regulatory Proteins
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Guanine Nucleotide Exchange Factors
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RNA, Messenger
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RNA, Small Interfering
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Rho Guanine Nucleotide Exchange Factors
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Connective Tissue Growth Factor
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Proto-Oncogene Proteins c-cbl
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ErbB Receptors
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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Death-Associated Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Extracellular Signal-Regulated MAP Kinases