Signaling by Type I and II cytokine receptors: ten years after

Gadina, Massimo; Hilton, Douglas J.; Johnston, James A.; Morinobu, Akio; Lighvani, Arash; Zhou, Yongjie; Visconti, Roberta; O’Shea, John J.

doi:10.1016/s0952-7915(00)00228-4

Cited by 190 publications

(150 citation statements)

References 98 publications

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“…47 A unifying hypothesis may envisage a primary activation brought about by HCV on members of the SOCS family in order to inhibit the interferon ␣ signaling as a mechanism of escaping to innate immunity. The simultaneous impairment of insulin signaling would be a necessary consequence due to the promiscuity of certain signal transducers shared by the 2 pathways, notably some members of the SOCS family, although the implication of other factors cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

et al. 2007

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Both molecular and clinical evidence support a link between HCV infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 3a and 1b with the insulin-signaling pathway. We measured the expression levels of insulin receptor substrate 1 (IRS-1), IRS-2, and other factors involved in the insulin signal pathway in a human hepatoma cell line (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by molecular biology and biochemical techniques. The IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotypes 3a and 1b, as compared to cells transfected with the empty vector. However, while the core protein of genotype 3a promoted IRS-1 degradation through the downregulation of peroxisome proliferator-activated receptor ␥ (PPAR␥) and by upregulating the suppressor of cytokine signal 7 (SOCS-7), the core protein of genotype 1b activated the mammalian target of rapamycin (mTOR). We confirmed these findings by using agonists for PPAR␥ (rosiglitazone) or short interfering RNAs for SOCS-7. Conclusion: Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype-specific mechanisms.

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Section: Discussionmentioning

confidence: 99%

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

et al. 2007

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“…Receptor-associated phosphorylated Stats then dimerize via SH2-phosphotyrosyl interactions, and translocate to the nucleus, where they bind specific promoter sequences, thereby regulating gene expression. (reviewed by Gadina et al [48]). It is now clear that ligand-induced chemokine receptor activation can also invoke Jak-Stat signaling, perhaps by a mechanism that requires receptor homodimerization and heterodimerization [39][40][41]47,49,50].…”

Section: The Jak-stat Connectionmentioning

confidence: 99%

Chemokines: attractive mediators of the immune response

Wong

Fish

2003

Seminars in Immunology

227

186

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“…Significant discoveries in this area include the identification of families of signaling molecules such as Janus (Jak) kinases and signal transducers and activators of transcription (STATs) which associate with a variety of cytokine receptors and initiate signaling cascades (Leonard and O'Shea, 1998;Rane and Reddy, 2000;Gadina et al, 2001). The complexity of this signaling is striking in that the same cytokine may activate different components in different cell types (Stahl et al, 1994) or diverse cytokines may employ the same or largely overlapping components (Ihle, 1995).…”

Section: Introductionmentioning

confidence: 99%

IL-6 mediated activation of STAT3 bypasses Janus kinases in terminally differentiated B lineage cells

et al. 2002

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Cytokine signaling generally occurs through receptors lacking tyrosine kinase activity. Aggregation of receptors leads to activation of receptor associated Janus kinases (Jaks) which in turn phosphorylate members of a family of transcription factors (STATs) that translocate to the nucleus and regulate gene expression. In the case of Interleukin-6 (IL-6), the consensus for signaling in B lineage cells has been that Jak1, Jak2 and Tyk2 are all phosphorylated upon ligand binding and participate in activation of downstream elements, in particular STAT3. In other cell types, Jak1 has been demonstrated to be absolutely required for IL-6 mediated activation of STAT3. In the present studies, we have identified a series of end stage B cell (plasma cell) lines that fail to express Jak1, but phosphorylate STAT3 in response to IL-6. No evidence was found for a requirement of other Jak family members in the activation of STAT3. STAT3 tyrosine phosphorylation was inhibited in a dose dependent manner by the MEK inhibitor U0126, but not by inhibitors of PI-3K or Src kinases. Moreover, STAT3 phosphorylation was similarly inhibited in lines expressing Jak1 wherein Jak1 was phosphorylated upon IL-6 stimulation and Jak1 phosphorylation was not inhibited by U0126. These results indicate that the MAPK pathway plays a critical role in IL-6 mediated tyrosine phosphorylation of STAT3 and suggests that Jak kinases may not be required in this cascade. Thus, it may be important to re-evaluate the role of Jak kinases in other cytokine signaling pathways as well.

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Signaling by Type I and II cytokine receptors: ten years after

Cited by 190 publications

References 98 publications

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

Chemokines: attractive mediators of the immune response

IL-6 mediated activation of STAT3 bypasses Janus kinases in terminally differentiated B lineage cells

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