Association of Transcription Factor APRF and Protein Kinase Jak1 with the Interleukin-6 Signal Transducer gp130

Lütticken, Claudia; Wegenka, Ursula; Yuan, Juping; Buschmann, Jan; Schindler, Christian; Ziemiecki, Andrew; Harpur, Ailsa G.; Wilks, Andrew F.; Yasukawa, Kiyoshi; Taga, Tetsuya; Kishimoto, Tadamitsu; Barbieri, Giovanna; Pellegrini, Sandra; Sendtner, Michael; Heinrich, Peter C.; Horn, Friedemann

doi:10.1126/science.8272872

Cited by 765 publications

(510 citation statements)

References 25 publications

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“…IL-3/IL-5/GMCSF activation of hematopoietic cells appears to result predominantly in the activation of JAK-2, although JAK-1 and TYK-2 have also been found to be activated in certain cell systems Quelle et al, 1994;Lutticken et al, 1994;Chaturvedi et al, 1997Chaturvedi et al, , 1998Jaster et al, 1997). The membrane proximal region of the IL-3R b c chain is involved in association with the N-terminal region of JAK2.…”

Section: Stat Signaling Pathwaysmentioning

confidence: 99%

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

et al. 2000

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Hematopoiesis is the cumulative result of intricately regulated signal transduction cascades that are mediated by cytokines and their cognate receptors. Proper culmination of these diverse signaling pathways forms the basis for an orderly generation of di erent cell types and aberrations in these pathways is an underlying cause for diseases such as cancer. Over the past several years, downstream events initiated upon cytokine/ growth factor stimulation have been a major focus of biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of novel transcription factors, termed signal transducers and activators of transcription (STATs) appear to orchestrate the downstream events propagated by cytokine/growth factor interactions with their cognate receptors. Until recently, the JAK proteins were considered to be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. However, over the past few years, increasing evidence has accumulated which indicates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulation. Studies have demonstrated that the Src-family of tyrosine kinases can phosphorylate and activate certain STAT proteins, in lieu of JAK kinases. In such a scenario, JAK kinases may be more crucial to phosphorylation of the cytokine/growth factor receptors and in the process create docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Tyrosine phosphorylation and activation of STAT proteins can be achieved either by JAKs or Src-kinases depending on the nature of STAT that is being activated. This forms the basis for the JAK-Src-STAT model proposed in this review. The concerted action of JAK kinases, members of the Src-kinase family and STAT proteins, leads to cell proliferation and cell survival, the end-point of the cytokine/growth factor stimulus.

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Section: Stat Signaling Pathwaysmentioning

confidence: 99%

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

et al. 2000

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“…The members of this cytokine family have pro-as well as anti-inflammatory properties and are major factors in haematopoiesis, and in acute phase and immune responses. The major step in IL-6-type cytokine signalling is the rapid activation of the Janus family tyrosine kinases (JAK proteins) by binding to the signal transducing proteins gp130, LIF receptor and OSM receptor [3][4][5] . The role played by JAK1 is essential because, in cells lacking JAK1, IL-6 signal transduction is greatly impaired 6,7 .…”

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confidence: 99%

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

et al. 2012

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Interleukin-6 (IL-6) and c-src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-src stimulates IL-6 expression through the sTAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions.

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“…For example, Tyk2 interacts with a domain of IFN-␣R␣, the ␣-chain of the IFN-␣R (also designated as IFNAR1 or IFN-␣R1), which has only distant homology with the box 1 or box 2 motifs (25,26). Jak1 is activated by multichain receptors such as the IL-6 group of cytokines (IL-6, leukemia inhibitory factor, ciliary neurotrophic factor, oncostatin M), IFN-␣, IFN-␥, IL-10, and those cytokine receptors that belong to the IL-2 family (IL-2, IL-4, IL-7, IL-9, and IL-15) (19,20,(27)(28)(29)(30)(31)(32)(33). The Jak1 binding site on cytokine receptors has been explored in only a few cases.…”

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confidence: 99%

Two Distinct Domains Within the N-Terminal Region of Janus Kinase 1 Interact with Cytokine Receptors

Usacheva

Witte

Colamonici

2002

The Journal of Immunology

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The interaction between receptors and kinases of the Janus kinase (Jak) family is critical for signaling by growth factors, cytokines, and IFNs. Therefore, the characterization of the domains involved in these interactions is pivotal not only in understanding kinase activation but also in the development of drugs that mimic or inhibit signaling. In this report, we have characterized the domains of Jak1 required to associate with distinct cytokine receptor subunits: IFN-αRβL, IFN-γRα, IL-10Rα, IL-2Rβ, and IL-4Rα. We demonstrate that two regions of Jak1 are necessary for the interaction with cytokine receptors. First, a common N-terminal region that includes Jak homology (JH) domain 7 and the first 19 aa of JH6, and, second, a C-terminal region (JH6–3) that was different for distinct receptors. The contribution of the two different regions of Jak1 to cytokine receptor binding was also variable. Deletion of JH7–6 impaired the association of IL-2Rβ and IL-4Rα chains with Jak1 but did not have a major impact on the binding of Jak1 to IFN-αRβL or IL-10Rα. Interestingly, regardless of the effect on receptor binding, removal of JH7–6 completely abrogated kinase activation, indicating that this domain is required for ligand-driven kinase activation and, thus, for proper signaling through cytokine receptors.

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Association of Transcription Factor APRF and Protein Kinase Jak1 with the Interleukin-6 Signal Transducer gp130

Cited by 765 publications

References 25 publications

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

Two Distinct Domains Within the N-Terminal Region of Janus Kinase 1 Interact with Cytokine Receptors

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