A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.

Guschin, Dmitry; Rogers, Neil C.; Briscoe, James; Witthuhn, Bruce A.; Watling, Diane; Horn, Friedemann; Pellegrini, Sandra; Yasukawa, Kiyoshi; Heinrich, Peter C.; Stark, George R.

doi:10.1002/j.1460-2075.1995.tb07128.x

Cited by 398 publications

(305 citation statements)

References 43 publications

Supporting

Mentioning

289

Contrasting

Unclassified

Order By: Relevance

“…2C4 and ␥2A were maintained in 400 g/ml G418, and U1D and U4A were maintained in Hygromycin (250 g/ml). U4A cells stably transfected with JAK1 (U4/J1) or JAK2 (U4/J2) were maintained in both G418 and Hygromycin at the above concentrations (50). U4A cells stably transfected with TYK2 (U4/T2) were maintained in Hygromycin (as above) and Puromycin (0.5 g/ml).…”

Section: Methodsmentioning

confidence: 99%

Janus Kinase-dependent Activation of Insulin Receptor Substrate 1 in Response to Interleukin-4, Oncostatin M, and the Interferons

Burfoot

Rogers

Watling

et al. 1997

Journal of Biological Chemistry

115

View full text Add to dashboard Cite

In addition to a role in response to insulin and insulinlike growth factors, insulin receptor substrate 1 (IRS-1) is phosphorylated in response to IL-4, the interferons (IFNs) and oncostatin M (OSM). Here mutant cell lines lacking JAK1, JAK2, or Tyk2 were used to determine the role(s) of the Janus kinase (JAK) family of protein-tyrosine kinases in IRS-1 phophorylation. 32D cells, which do not express IRS proteins, were analyzed for any requirement for these proteins in response to the IFNs. For the mutant human fibrosarcoma cell lines, phosphorylation of IRS-1 through the insulin-like growth factor receptor is independent of JAK1, JAK2, or Tyk2. In contrast, phosphorylation of IRS-1 mediated by the Type I IFNs, IL-4, and OSM is JAK-dependent. For the ␣␤-IFNs, activation of IRS-1 is dependent on JAK1 and Tyk2, consistent with the interdependence of these kinases in the IFN-␣␤ response. Neither IRS-1 nor IRS-2 was detectably activated by IFN-␥. Consistent with this, activation of neither IRS proteins appears to be an absolute requirement for an antiproliferative or an antiviral response to the IFNs. For IL-4 and OSM phosphorylation of IRS-1 in the human fibrosarcoma cells is largely dependent on JAK1 but can also be mediated through Tyk2 or JAK2. Activation of phosphatidylinositol 3 -kinase in response to IL-4 and OSM, at least, was also JAK-dependent. The JAKs are, therefore, required not only for STAT activation but also for the activation, through a variety of different types of cytokine receptor, of an additional signaling pathway(s) through IRS-1 and phosphatidylinositol 3 -kinase.Receptors that have an intrinsic tyrosine kinase domain recruit and activate a variety of signal transducers. Insulin receptor substrate 1 (IRS-1) 1 is a cytosolic protein of ϳ180 kDa in mass that is tyrosyl-phosphorylated at multiple sites through activated insulin and insulin-like growth factor 1 (IGF-1) receptors (1, 2). An L(X) 4 NPXY(p)XSXP motif has been identified in the insulin receptor as being important for the recruitment of the IRS proteins. IRS-1 contains multiple YMXM and YXXM tyrosine motifs, which when phosphorylated can recruit Src homology 2 domain-containing proteins, including the p85␣ regulatory subunit of PI 3Ј-kinase, SHP-2, Grb-2, Crk, and Nck (3, 4). Phosphorylated IRS-1, therefore, can mediate a variety of responses including a mitogenic response and activation of PI 3Ј-kinase.Common themes involving the role of tyrosine kinases and proteins with Src homology 2 domains have emerged to describe broadly the mechanism of signal transduction by many growth factors and cytokines. Signal transduction pathways utilizing the JAK (Janus kinase) family of protein-tyrosine kinases and the STATs (signal transducers and activators of transcription) are activated in response to polypeptide ligands including many cytokines, some growth factors and the interferons (IFNs). STAT activation mediated through the JAKs occurs in receptor complexes at the cell membrane. There are four known mammalian JAKs: JAK1, JAK2, JAK3, and T...

show abstract

Section: Methodsmentioning

confidence: 99%

Janus Kinase-dependent Activation of Insulin Receptor Substrate 1 in Response to Interleukin-4, Oncostatin M, and the Interferons

Burfoot

Rogers

Watling

et al. 1997

Journal of Biological Chemistry

115

View full text Add to dashboard Cite

show abstract

“…We next examined whether Isl1 interacted with the full-length Jaks. We chose Jak1 for further studies because Jak1 plays a predominant role in the IL-6 signaling (Guschin et al, 1995). We found that Isl1 bound to the full-length Jak1 but not to a kinase-inactive Jak1 ( Figure 1B).…”

Section: Identification Of Isl1 As a Jak Interacting Proteinmentioning

confidence: 99%

The LIM/Homeodomain Protein Islet1 Recruits Janus Tyrosine Kinases and Signal Transducer and Activator of Transcription 3 and Stimulates Their Activities

Hao

Novotny‐Diermayr

Bian

et al. 2005

MBoC

View full text Add to dashboard Cite

Islet1 (Isl1) belongs to the LIM homeodomain transcription factor family. Its roles in differentiation of motor neurons and organogenesis of pancreas and heart have been revealed. However, less is known about its regulatory mechanism and the target genes. In this study, we identified interactions between Isl1 and Janus tyrosine kinase (JAK), as well as signal transducer and activator of transcription (Stat)3, but not Stat1 and Stat5, in mammalian cells. We found that Isl1 not only forms a complex with Jak1 and Stat3 but also triggers the tyrosine phosphorylation of Jak1 and its kinase activity, thereby elevating the tyrosine phosphorylation, DNA binding activity, and target gene expression of Stat3. In vivo, the tyrosine-

show abstract

“…Downstream pathways of signal transduction and gene modulation by IL-6 which are activated by gp130 dimerization include activation of tyrosine kinases Jak1, Jak2 and Tyk2 (Guschin et al, 1995;Narazaki et al, 1994;Stahl et al, 1994), but also of Btk, Tec and Fes (Matsuda et al, , 1995, as well as activation of MAP kinase-dependent pathways (Akira et al, 1995). Several Signal Transducer and Transcriptional Activator (Stat) proteins are phosphorylated in response to IL-6 including gp130-bound Stat3/APRF (Akira et al, 1994;Harroch et al, 1994b;Zhong et al, 1994;Stahl et al, 1995) as well as Stat1 (Harroch et al, 1994a,b;Zhong et al, 1994) and Stat5b (Ripperger et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Unmasking by soluble IL-6 receptor of IL-6 effect on metastatic melanoma: growth inhibition and differentiation of B16-F10.9 tumor cells

Katz

Harroch

et al. 1997

Oncogene

View full text Add to dashboard Cite

Interleukin-6 (IL-6) inhibits the growth of melanocytes and of early stage melanoma cells, but not that of advanced melanoma cells. The in vitro IL-6 response can be restored in the highly metastatic melamona B16-F10.9 by addition of recombinant soluble IL-6 receptor a-chain (sIL-6R). The F10.9 cells then undergo irreversible growth-arrest and show increased adherence with changes from epithelioid to spindleoid morphology. The sIL-6R is required for IL-6 to induce a sustained activation of the various Stat transcription factors which bind to speci®c IL-6 inducible enhancers. The sIL-6R and IL-6 combination causes an increase in the level of the anti-oncogenic transcription factor IRF-1 protein and DNA-binding, which remain elevated for 24 h. The promoter activity of the anti-oncogenic p21/Waf-1/Cip-1 gene is induced and accumulation of the p21 protein is observed. These results illustrate the potent agonist activity of sIL-6R on molecular pathways which could mediate the growth-arrest and di erentiation of the metastatic melanoma cells. Previously observed antimetastatic e ects of IL-6 therapy in mice bearing F10.9 tumors may be at least partly due to direct growth inhibition and di erentiation elicited by sIL-6R present in biological¯uids.

show abstract

A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.

Cited by 398 publications

References 43 publications

Janus Kinase-dependent Activation of Insulin Receptor Substrate 1 in Response to Interleukin-4, Oncostatin M, and the Interferons

Janus Kinase-dependent Activation of Insulin Receptor Substrate 1 in Response to Interleukin-4, Oncostatin M, and the Interferons

The LIM/Homeodomain Protein Islet1 Recruits Janus Tyrosine Kinases and Signal Transducer and Activator of Transcription 3 and Stimulates Their Activities

Unmasking by soluble IL-6 receptor of IL-6 effect on metastatic melanoma: growth inhibition and differentiation of B16-F10.9 tumor cells

Contact Info

Product

Resources

About