An Epidermal Growth Factor Receptor/Jak2 Tyrosine Kinase Domain Chimera Induces Tyrosine Phosphorylation of Stat5 and Transduces a Growth Signal in Hematopoietic Cells

Nakamura, N; Chin, Hiroshi; Miyasaka, Nobuyuki; Miura, Osamu

doi:10.1074/jbc.271.32.19483

Cited by 82 publications

(59 citation statements)

References 41 publications

(47 reference statements)

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“…EGFR can induce the downstream activation of several important intermediate signal transduction kinases, including Ras, 28 phosphotidylinositol-3 kinase (PI3K), 29 MEK 30 and Janus kinase (JAK). 31 These signal components in turn have been shown to be able to activate several signal pathways that activate transcription factors, such as AP-1, 32 NF-B 33,34 and signal transduction and transcription factor-3 (STAT3). 35,36 In our study, we examined the effect of antagonists of EGFR, PI3K and MEK on NF-B and AP-1 activation and IL-8 and VEGF expression in HNSCC cell lines UM-SCC-9 and 11B.…”

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confidence: 99%

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Bancroft

Chen

Yeh

et al. 2002

Intl Journal of Cancer

218

190

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Key words: EGFR; NF-B; AP-1; IL-8; VEGF; PI3K; MEK; HNSCCIncreased angiogenesis is critical to tumor progression and metastasis, and we and others have shown that expression of members of the C-X-C cytokine and vascular endothelial growth factor families such as IL-8, growth regulated oncogene-1 (Gro 1) and VEGF can promote angiogenesis, tumorigenesis and metastatic tumor progression. 1-3 The expression of multiple factors with proangiogenic activity by cancer cells poses a significant obstacle to effective therapy with agents targeted toward individual factors and receptors. Identification of common mechanism(s) underlying expression of such a diversity of factors could guide the development of therapy using fewer selective agents. We previously observed that IL-8, VEGF and other cytokines are coexpressed and often vary concurrently in serum and supernatants from cell lines from different patients with head and neck squamous cell carcinoma (HNSCC), 4,5 suggesting that these factors could be regulated by common signal pathways or transcription factors.Examination of the regulatory region of many proinflammatory cytokines and proangiogenic factors reveals that they share common promoter sites for transcription factors such as nuclear factor-B (NF-B) and/or activator protein-1 (AP-1), which can be activated by injury, cytokines and growth factors. 6 We found that differences in expression of these cytokines in different cancers was often related to differences in constitutive activation of both NF-B and AP-1. 6 Inhibition of NF-B activation by expression of a dominant negative inhibitor-B or pharmacologic agents was found to inhibit expression of IL-8 and other proinflammatory and proangiogenic cytokines, 7-10 as well as tumorigenesis and angiogenesis in vivo. 7,9 Inhibition of activation of extracellular signalregulated kinase (ERK) and AP-1 with antagonists of mitogenactivated/extracellular signal-regulated kinase (MEK) partially inhibited expression of both IL-8 and VEGF. 10 These results provided evidence that at least 2 signal pathways upstream of NF-B and AP-1 make important contributions to expression of these angiogenesis factors.We have recently examined the contribution of several factors that may contribute to upstream signal activation of NF-B and AP-1 and expression of IL-8 and VEGF. We found that IL-1␣ expressed by HNSCC promotes autocrine activation of NF-B and AP-1, expression of IL-8 and cell survival. 11 Expression of IL-1 receptor antagonist inhibited NF-B reporter activity and IL-8 expression by 60 -80%, indicating that IL-1␣ is a major contributor to constitutive activation of NF-B and IL-8. HNSCC were also found to express c-MET, a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). 12 Increased expression of HGF/SF was detected together with IL-8 and VEGF in serum of patients with HNSCC, and recombinant HGF and HGF from stromal fibroblasts was found to further induce IL-8 and VEGF expression by human HNSCC lines. Inhibitors of MEK and Abbreviations: AP-1, activator...

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confidence: 99%

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Bancroft

Chen

Yeh

et al. 2002

Intl Journal of Cancer

218

190

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“…Because tyrosine phosphorylation of Jak2 closely correlates with the tyrosine kinase activity of Jak2 (Witthuhn et al, 1993;Ihle, 1995;Nakamura et al, 1996), we first examined the tyrosine phosphorylation status of the GyrB-Jak2 fusion proteins by immunoprecipitation followed by Western blotting with anti-phosphotyrosine antibody (4G10). As shown in Figure 2A, addition of coumermycin induced tyrosine phosphorylation of the GNJK (100 kDa) and the GIJW (160 kDa) fusion proteins but not the GNJW fusion protein or the endogenous Jak2.…”

Section: Coumermycin-induced Tyrosine Phosphorylation Of Gyrb-jak2 Fumentioning

confidence: 99%

Activation and Functional Analysis of Janus Kinase 2 in BA/F3 Cells Using the Coumermycin/Gyrase B System

Mohi

Arai

Watanabe

1998

MBoC

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Janus kinase 2 (Jak2) protein tyrosine kinase plays an important role in interleukin-3-or granulocyte-macrophage colony-stimulating factor-mediated signal transduction pathways leading to cell proliferation, activation of early response genes, and inhibition of apoptosis. However, it is unclear whether Jak2 can activate these signaling pathways directly without the involvement of cytokine receptor phosphorylation. To investigate the specific role of Jak2 in the regulation of signal transduction pathways, we generated gyrase B (GyrB)-Jak2 fusion proteins, dimerized through the addition of coumermycin. Coumermycin induced autophosphorylation of GyrB-Jak2 fusion proteins, thus bypassing receptor activation. Using different types of chimeric Jak2 molecules, we observed that although the kinase domain of Jak2 is sufficient for autophosphorylation, the N-terminal regions are essential for the phosphorylation of Stat5 and for the induction of short-term cell proliferation. Moreover, coumermycin-induced activation of Jak2 can also lead to increased levels of c-myc and CIS mRNAs in BA/F3 cells stably expressing the Jak2 fusion protein with the intact N-terminal region. Conversely, activation of the chimeric Jak2 induced neither phosphorylation of Shc or SHP-2 nor activation of the c-fos promoter. Here, we showed that the GyrB-Jak2 system can serve as an excellent model to dissect signals of receptor-dependent and -independent events. We also obtained evidence indicating a role for the N-terminal region of Jak2 in downstream signaling events.

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“…Although precise mechanisms of`re-activation' of Akt and STAT5 in cells expressing BCR/ABL SH3+SH2 mutants are not known, they were associated with the activation of PI-3k and Jak-2, the two direct upstream activators of Akt and STAT5, respectively (Franke et al, 1995;Nakamura et al, 1996). In addition, the ABL kinase-dependent`reactivation' of Akt and STAT5 in clones expressing BCR/ABL SH3+SH2 mutant was accompanied by phosphorylation of the common b subunit of IL-3/IL-5/GM-CSF receptor, suggesting the involvement of IL-3-dependent signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells

2000

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Our previous study indicated that BCR/ABL SH2 domain and BCR/ABL SH3 domain+SH2 domain complex are required for immediate activation of the phosphatidylinositol-3 kinase PI-3k)? Akt serine/threonine kinase pathway and of the signal transducer and activator of transcription 5 (STAT5), respectively, in hematopoietic cells. We show here that the defect in activation of PI-3k/Akt by BCR/ABL DSH2 mutant (SH2 domain deleted) and of STAT5 by BCR/ABL DSH3+DSH2 mutant (SH3 and SH2 domains deleted) is not permanent and both Akt and STAT5 could be`reactivated' by in vitro culture. This phenomenon was responsible for increased resistance to apoptosis, growth factor-independent proliferation and leukemogenesis in SCID mice. Incubation of cells with BCR/ABL tyrosine kinase inhibitor STI571 abrogated the`re-activation' of Akt or STAT5 by BCR/ABL SH3+SH2 mutants in some clones, in the others Akt and STAT5 activation became independent on BCR/ABL kinase activity. The immediate upstream activators of Akt and STAT5 such as PI-3k and Jak-2 were also activated. In addition, the common b subunit of IL-3/IL-5/GM-CSF receptor was tyrosine phosphorylated in the clones in which`reactivation' was dependent on the BCR/ABL kinase activity. These results suggested that`re-activation' of Akt and STAT5, in the absence of functional BCR/ABL SH3+SH2 domains, may be achieved by two di erent mechanisms: (i) BCR/ABL kinase-dependent activation of alternative pathway(s) and (ii) additional genetic changes stimulating Akt and STAT5 independently of BCR/ABL. Oncogene (2000) 19, 4117 ± 4124.

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An Epidermal Growth Factor Receptor/Jak2 Tyrosine Kinase Domain Chimera Induces Tyrosine Phosphorylation of Stat5 and Transduces a Growth Signal in Hematopoietic Cells

Cited by 82 publications

References 41 publications

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Activation and Functional Analysis of Janus Kinase 2 in BA/F3 Cells Using the Coumermycin/Gyrase B System

Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells

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