Interleukin-2 (IL-2) receptor-betagamma signalling is activated by c-Kit in the absence of IL-2, or by exogenous IL-2 via JAK3/STAT5 in human papillomavirus-associated cervical cancer.
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.
Rocha-Zavaleta
Leticia
L
Department of Molecular Biology and Biotechnology, Institute of Biomedical Research, National University of Mexico, Circuito Escolar s/n, Ciudad Universitaria, Mexico City.
Huitron
Carlos
C
Cacéres-Cortés
Julio R
JR
Alvarado-Moreno
José A
JA
Valle-Mendiola
Arturo
A
Soto-Cruz
Isabel
I
Weiss-Steider
Benny
B
Rangel-Corona
Rosalva
R
D002277:Carcinoma / Q000276:immunology* / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D053616:Janus Kinase 3; D008894:Milk Proteins / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000821:virology
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D008894:Milk Proteins; D021122:Protein Subunits; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C507933:JAK3 protein, human; D053616:Janus Kinase 3