A role for Janus kinases in crosstalk between ErbB3 and the interferon-alpha signaling complex in myeloma cells.
Receptor crosstalk is an emerging and recurrent theme in cytokine and growth factor signaling; however, insight into the mechanism(s) underlying these interactions remains limited. Recently, we reported that crosstalk occurs between ErbB3 and the interferon alpha (IFN-alpha) signaling complex in the myeloma cell line KAS-6/1 and that this crosstalk contributes to the regulation of cell proliferation. In this study, we examined the mechanism underlying the transactivation of ErbB3 in the IFN-alpha growth-responsive KAS-6/1 cells. The examination of IFN-alpha receptor 1 and 2 (IFNAR1 and IFNAR2) levels revealed that the KAS-6/1 cell line overexpresses IFNAR1 relative to other myeloma cell lines that are growth arrested by IFN-alpha. Subsequent investigation of Tyk2, which is constitutively associated with IFNAR1, demonstrated that Tyk2 activation is uniquely sustained in the KAS-6/1 cell line following IFN-alpha stimulation. Interestingly, silencing of Tyk2 expression via siRNA resulted in attenuation of ErbB3 transactivation. However, inhibition of Jak1 expression also decreased IFN-alpha-induced tyrosine phosphorylation of ErbB3. Finally, siRNA downregulation of Tyk2 and Jak1 was found to decrease IFN-alpha-stimulated proliferation. These findings validate our previous report of ErbB3 involvement in IFN-alpha-induced proliferation and further suggest that both Janus kinase members, Tyk2 and Jak1, play a role in the transactivation of ErbB3 in this model system.
Walters
Denise K
DK
Department of Immunology, Tumor Biology Program, Mayo Graduate and Medical Schools, Mayo Clinic/Foundation, Rochester, MN 55905, USA.
Jelinek
Diane F
DF
D001483:Base Sequence; D002455:Cell Division; D004261:DNA Replication; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008565:Membrane Proteins; D009101:Multiple Myeloma; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D011505:Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3