Walters Denise K, Jelinek Diane F
Department of Immunology, Tumor Biology Program, Mayo Graduate and Medical Schools, Mayo Clinic/Foundation, Rochester, MN 55905, USA.
Oncogene. 2004 Feb 12;23(6):1197-205. doi: 10.1038/sj.onc.1207203.
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.
受体间相互作用是细胞因子和生长因子信号传导中一个新出现且反复出现的主题；然而，对这些相互作用背后机制的了解仍然有限。最近，我们报道在骨髓瘤细胞系KAS-6/1中，ErbB3与干扰素α（IFN-α）信号复合物之间存在相互作用，且这种相互作用有助于调节细胞增殖。在本研究中，我们研究了IFN-α生长反应性KAS-6/1细胞中ErbB3反式激活的机制。对IFN-α受体1和2（IFNAR1和IFNAR2）水平的检测显示，与其他被IFN-α阻滞生长的骨髓瘤细胞系相比，KAS-6/1细胞系中IFNAR1过表达。随后对与IFNAR1组成性相关的Tyk2的研究表明，在IFN-α刺激后，Tyk2的激活在KAS-6/1细胞系中独特地持续存在。有趣的是，通过小干扰RNA（siRNA）沉默Tyk2表达导致ErbB3反式激活减弱。然而，抑制Jak1表达也降低了IFN-α诱导的ErbB3酪氨酸磷酸化。最后，发现通过siRNA下调Tyk2和Jak1可降低IFN-α刺激的细胞增殖。这些发现证实了我们之前关于ErbB3参与IFN-α诱导的增殖的报道，并进一步表明，在该模型系统中，Janus激酶家族成员Tyk2和Jak1在ErbB3的反式激活中均发挥作用。
