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A Role for Janus Kinases in Crosstalk Between Erbb3 and the Interferon-Alpha Signaling Complex in Myeloma Cells

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A Role for Janus Kinases in Crosstalk Between Erbb3 and the Interferon-Alpha Signaling Complex in Myeloma Cells Oncogene (2004) 23, 1197–1205 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc A role for Janus kinases in crosstalk between ErbB3 and the interferon-alpha signaling complex in myeloma cells Denise K Walters1 and Diane F Jelinek*,1 1Department of Immunology, Tumor Biology Program, Mayo Graduate and Medical Schools, Mayo Clinic/Foundation, Rochester, MN 55905, USA Receptor crosstalk is an emerging and recurrent theme in activation of a particular signaling cascade(s) and the cytokine and growth factor signaling; however,insight resulting biological response (Dumont et al., 2001). into the mechanism(s) underlying these interactions However, over the last decade it has become clear that remains limited. Recently,we reported that crosstalk this process may be much more complex than initially occurs between ErbB3 and the interferon alpha (IFN-a) anticipated. In fact, numerous reports have now shown signaling complex in the myeloma cell line KAS-6/1 and that biological responses may be brought about through that this crosstalk contributes to the regulation of cell receptor crosstalk or the transactivation of additional proliferation. In this study,we examined the mechanism and often unrelated receptor subtypes (reviewed by Hill, underlying the transactivation of ErbB3 in the IFN-a 1998). For example, in rat hepatocytes binding of growth-responsive KAS-6/1 cells. The examination of growth hormone (GH) to its receptor was shown not IFN-a receptor 1 and 2 (IFNAR1 and IFNAR2) levels only to result in the activation of the GH receptor but revealed that the KAS-6/1 cell line overexpresses also in the tyrosine phosphorylation of the epidermal IFNAR1 relative to other myeloma cell lines that are growth factor receptor (EGFR) (Yamauchi et al., 1997). growth arrested by IFN-a. Subsequent investigation of Interestingly, Jak2 appeared to play a role in the Tyk2,which is constitutively associated with IFNAR1, transactivation of the EGFR following GH stimulation. demonstrated that Tyk2 activation is uniquely sustained in In addition, the phosphorylation of the EGFR was also the KAS-6/1 cell line following IFN-a stimulation. shown to be required for GH-induced activation of the Interestingly,silencing of Tyk2 expression via siRNA MAP kinase pathway. resulted in attenuation of ErbB3 transactivation. How- During tumorigenesis and/or tumor progression, ever,inhibition of Jak1 expression also decreased IFN- a- malignant cells frequently overexpress or acquire induced tyrosine phosphorylation of ErbB3. Finally, atypical expression of one or more signaling receptors. siRNA downregulation of Tyk2 and Jak1 was found to Given the fact that a variety of receptors have now been decrease IFN-a-stimulated proliferation. These findings shown to be able to act in a nonlinear fashion, receptor validate our previous report of ErbB3 involvement in IFN- crosstalk has emerged as a potential mechanism by a-induced proliferation and further suggest that both which tumor cells may potentially amplify and/or Janus kinase members,Tyk2 and Jak1,play a role in the diversify their responses to growth factors/cytokines transactivation of ErbB3 in this model system. (Jelinek et al., 2003). To acquire an understanding of Oncogene (2004) 23, 1197–1205. doi:10.1038/sj.onc.1207203 growth and survival control in malignant cells, it is Published online 1 December 2003 therefore imperative to comprehend fully linear as well as potential nonlinear interactions in transformed Keywords: Jak1; Tyk2; ErbB3; interferon-alpha; multi- cells. ple myeloma In this regard, we have had a long-standing interest in the growth regulation of multiple myeloma (MM), a typically fatal plasma cell malignancy. Thus, we have been actively investigating the ability of the tumor cells Introduction in this disease to signal in a nonlinear fashion. More specifically we have had a particular interest in Signal transduction pathways have classically been determining if receptor crosstalk plays a role in the described as a linear sequence of events that involve ability of IFN-a to modulate myeloma cell growth in a the interaction of a ligand with a specific receptor, variable manner (Brenning et al., 1985; Jourdan et al., 1991; Westendorf et al., 1996; Jelinek et al., 1997). Recently, we reported detection of ErbB3, a member of *Correspondence: DF Jelinek, 200 First Street SW, Rochester, the ErbB family member, on the MM cell line KAS-6/1, MN 55905, USA; E-mail: [email protected] which is growth responsive to IFN-a. Based on the fact This work was supported by National Institutes of Health Grants CA62242 and CA62228 that ErbB family members are known to play an Received 28July 2003; revised 8September 2003; accepted 9 September important role in several cancers (i.e. breast, prostate) 2003 and that various ErbB members have previously been Jak kinases mediate crosstalk in myeloma cells DK Walters and DF Jelinek 1198 suggested to be potentially involved in the development Materials and methods and progression of a subset of B-lymphoblastic leuke- mias and MM (Buhring et al., 1995; Klein, B., 2003, Cell lines, culture medium and reagents personal communication), we were interested in deter- The myeloma cell lines ANBL-6, DP-6, KAS-6/1, and KP-6 mining if ErbB3 may play a role in the growth were derived from primary patient myeloma cells and all have regulation of the KAS-6/1 cell line. Interestingly, we been described previously (Westendorf et al., 1996; Jelinek discovered that crosstalk occurs between the atypically et al., 1997). These cell lines were maintained as previously expressed ErbB3 molecule and the IFN-a receptor in described (Arora et al., 1999). Recombinant purified IFN-a2b these cells. Furthermore, we were also able to demon- (Schering, Kenilworth, NJ) was used at 10 000 U/ml in strate through siRNA-mediated downregulation of immunoprecipitation experiments and at 1000 U/ml in DNA synthesis assays. Interleukin-6 (IL-6) (Novartis Pharma, Basel, ErbB3 that this crosstalk does indeed contribute to the Switzerland) was used at 1 ng/ml in DNA synthesis assays. IFN-a-induced proliferative ability of these cells (Wal- ters et al., 2003). Immunofluorescence analysis Despite the abundance of evidence supporting the incidence and importance of receptor crosstalk, few Analysis of cell surface protein expression was determined by studies have thoroughly examined the mechanism by immunofluorescence. Briefly, 1 Â 106 cells were incubated with which receptor crosstalk is facilitated. However, based mAbs to IFNAR1 (R&D Systems Inc., Minneapolis, MN, on our knowledge of receptor signaling and previous USA), IFNAR2 (Research Diagnostics Inc., Flanders, NY, USA), or ErbB3 (Neomarkers, Fremont, CA, USA) for 30 min receptor crosstalk reports, we hypothesized that there on ice in PBS/2% FCS, washed and then incubated with PE- are at least two mechanisms by which receptor crosstalk conjugated goat anti-mouse IgG for 30 min (Biosource, most likely occurs. These mechanisms include direct Camarillo, CA, USA). Cells were then washed, fixed in 1% physical association of the receptors and/or lateral paraformaldehyde and analysed for immunofluorescence on a signaling by nonreceptor tyrosine kinases. As we FACSCAN flow cytometer (Becton Dickinson, Mountain were previously unable to detect a physical association View, CA, USA). Control Abs included mouse IgG1 and between ErbB3 and the IFN-a receptor (Walters IgG2a. Data were analysed using WinMDI 2.5 software. et al., 2003), we hypothesized that crosstalk must be mediated via lateral signaling by nonreceptor tyrosine Immunoprecipitation and immunoblotting kinases. Cells were cultured in IL-6-free medium supplemented with Similar to other cytokine receptors, the type I IFN 0.5% BSA prior to IFN-a addition. Cells (1.0–2.0 Â 107) were receptor is devoid of any intrinsic kinase activity lysed using RIPA lysis buffer (50 mM Tris pH 7.4, 150 mM (Novick et al., 1994). However, this deficiency is NaCl, 1% NP-40, 0.5% DOC, 0.1% SDS, 1 mM EDTA, overcome through utilization of the Jak-STAT pathway, 15 mM sodium molybdate, 1 mM NaF) or Brij lysis buffer which is comprised of a family of cytoplasmic non- (10 mM Tris pH 7.4, 150 mM NaCl, 0.5 mM CaCl2, 0.5 mM receptor tyrosine kinases called the Janus kinases (also MgCl2, 1% Brij-97) supplemented with protease inhibitors known as Jaks) and a family of SH2 domain containing (10 mg/ml leupeptin, 10 mg/ml aprotinin, 10 mg/ml pepstatin, proteins called signal transducers and activators of 2mM Na3VO4, and 1 mM PMSF). Lysates were cleared of insoluble material by centrifugation for 10 min at 14 000 r.p.m. transcription (STATs) (reviewed in Boundy and Kovar- Following centrifugation, 1 mg/ml of protein-specific antibody ik, 2002). Briefly, ligand binding induces transpho- (Jak1 or Tyk2; BD Biosciences, San Jose, CA, USA; ErbB3 or sphorylation and activation of Janus kinase family IFNAR1; Santa Cruz, CA, USA) bound to protein-A or members Tyk2 and Jak1, which are constitutively gammabind-G sepharose beads was added to lysates contain- associated with the a and b subunits of the IFN ing equal amounts of protein. The lysate and immune- signaling complex, respectively. Activated Tyk2 and complexes were then incubated with agitation for 2–4 h at Jak1 then rapidly phosphorylate specific tyrosine 41C. The resulting immunoprecipitates were then washed three residues on the receptor subunits allowing these times and resuspended in 25 mlof2Â SDS loading buffer, phosphorylated residues to serve as docking sites heated to 1001C for 5 min, resolved by SDS–PAGE and for members of the STAT family. Following docking transferred to Immobilon-P membranes (Millipore Corp., Bedford, MA, USA) for immunoblotting. Membranes were to receptors, the STAT proteins are phosphorylated blocked in 25 mM Tris-HCl (pH 7.2), 150 mM NaCl, 0.2% by Tyk2 and Jak1 allowing homo- or heterodimeriza- Tween (TBST) supplemented with 0.2% BSA for 1 h.
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