Abstract
Activation of the interleukin-2 receptor (IL-2R) induces signalling cascades promoting T cell proliferation. However, signal transduction pathways triggered in IL-2R-expressing solid tumours are unknown. This report shows that human papillomavirus (HPV)-associated cervical cancer cells express an IL-2R composed of beta and gamma chains (IL-2Rbetagamma), and that IL-2-mediated activation increases the phosphorylation of JAK3 and STAT5, stimulating cell proliferation. Interestingly, endogenous IL-2 is not produced by these cells, suggesting the activation of IL-2Rbetagamma by an alternative mechanism. Accordingly, we found that Stem Cell Factor (SCF)-activated c-Kit induces phosphorylation of the IL-2Rbeta chain in the absence of IL-2. Moreover, inhibition of IL-2Rbeta phosphorylation by blocking c-Kit tyrosine kinase activity abolishes both, IL-2 and SCF-mediated proliferation. Thus, these results demonstrate that IL-2 triggers a JAK3/STAT5 cascade in HPV-associated cervical cancer cells expressing IL-2Rbetagamma, and that this receptor can be alternatively activated by SCF-activated c-Kit in the absence of IL-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma / immunology*
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Carcinoma / virology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA-Binding Proteins / immunology*
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Enzyme Inhibitors / pharmacology
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / immunology
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Humans
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Interleukin-2 / immunology
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Interleukin-2 / pharmacology
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Janus Kinase 3
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Milk Proteins / immunology*
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Papillomaviridae / immunology*
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Phosphorylation / drug effects
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Protein Subunits / immunology
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Protein-Tyrosine Kinases / immunology*
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Proto-Oncogene Proteins c-kit / drug effects
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Proto-Oncogene Proteins c-kit / immunology*
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Receptors, Interleukin-2 / immunology*
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STAT5 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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Stem Cell Factor / metabolism
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Stem Cell Factor / pharmacology
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Trans-Activators / immunology*
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Uterine Cervical Neoplasms / immunology*
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Uterine Cervical Neoplasms / virology
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Interleukin-2
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Milk Proteins
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Protein Subunits
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Receptors, Interleukin-2
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STAT5 Transcription Factor
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Stem Cell Factor
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Trans-Activators
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-kit
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JAK3 protein, human
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Janus Kinase 3