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.