Interferonγ Activation of Raf-1 Is Jak1-dependent and p21ras-independent

Sakatsume, Minoru; Stancato, Louis F.; David, Michael; Silvennoinen, Olli; Saharinen, Pipsa; Pierce, Jacalyn H.; Larner, Andrew C.; Finbloom, D S

doi:10.1074/jbc.273.5.3021

Cited by 73 publications

(57 citation statements)

References 41 publications

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“…To this regard, type I IFNs have been shown to stimulate Raf and ERK activation in a Jak-dependent, but Ras-independent manner (Stancato et al, 1997;Sakatsume al, 1998). The cross-talk between the Jak/STAT and MEK/ERK pathway is further demonstrated by observation that stimulation with IFN-β can result in activation of ERK and its direct association with STAT1, as revealed by co-immunoprecipitation studies (David et al, 1995).…”

Section: Discussionmentioning

confidence: 96%

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

2000

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Summary Interferon (IFN)-α affects the growth, differentiation and function of various cell types by transducing regulatory signals through the Janus tyrosine kinase/signal transducers of activation and transcription (Jak/STAT) pathway. The signalling pathways employing the mitogenactivated ERK-activating kinase (MEK) and the extracellular-regulated kinase (ERK) are critical in growth factors signalling. Engagement of the receptors, and subsequent stimulation of Ras and Raf, initiates a phosphorylative cascade leading to activation of several proteins among which MEK and ERK play a central role in routing signals critical in controlling cell development, activation and proliferation. We demonstrate here that 24-48 h following treatment of transformed T-and monocytoid cell lines with recombinant human IFN-α2b both the phosphorylation and activity of MEK1 and its substrates ERK1/2 were reduced. In contrast, the activities of the upstream molecules Ras and Raf-1 were not affected. No effect on MEK/ERK activity was observed upon short-term exposure (1-30 min) to IFN. The anti-proliferative effect of IFN-α was increased by the addition in the culture medium of a specific inhibitor of MEK, namely PD98059. In conclusion, our results indicate that IFN-α regulates the activity of the MEK/ERK pathway and consequently modulates cellular proliferation through a Ras/Raf-independent mechanism. Targeting the MEK/ERK pathway may strengthen the IFN-mediated anti-cancer effect.

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Section: Discussionmentioning

confidence: 96%

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

2000

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“…Recent data also indicated that JAK proteins directly interact with p85 and activate PI 3-kinase (Migone et al, 1998;AlShami and Naccache, 1999). Interactions between STAT5 and JAK2 and JAK and Raf have been reported (Fujitani et al, 1997;Sakatsume et al, 1998). Relationships between Ras and PI 3-kinase have been also described indicating that these pathways are connected and probably regulate each other .…”

Section: Introductionmentioning

confidence: 97%

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

et al. 2000

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Cytokine-dependent activation of distinct signaling pathways is a common scheme thought to be required for the subsequent programmation into cell proliferation and survival. The PI 3-kinase/Akt, Ras/MAP kinase, Ras/ NFIL3 and JAK/STAT pathways have been shown to participate in cytokine mediated suppression of apoptosis in various cell types. However the relative importance of these signaling pathways seems to depend on the cellular context. In several cases, individual inhibition of each pathway is not su cient to completely abrogate cytokine mediated cell survival suggesting that cooperation between these pathways is required. Here we showed that individual inhibition of STAT5, PI 3-kinase or MEK activities did not or weakly a ected the IL-3 dependent survival of the bone marrow derived Ba/F3 cell line. However, the simultaneous inhibition of STAT5 and PI 3-kinase activities but not that of STAT5 and MEK reduced the IL-3 dependent survival of Ba/F3. Analysis of the expression of the Bcl-2 members indicated that phosphorylation of Bad and Bcl-x expression which are respectively regulated by the PI 3-kinase/Akt pathway and STAT5 probably explain this cooperation. Furthermore, we showed by co-immunoprecipitation studies and pull down experiments with fusion proteins encoding the GST-SH2 domains of p85 that STAT5 in its phosphorylated form interacts with the p85 subunit of the PI 3-kinase. These results indicate that the activations of STAT5 and the PI 3-kinase by IL-3 in Ba/F3 cells are tightly connected and cooperate to mediate IL-3-dependent suppression of apoptosis by modulating Bad phosphorylation and Bcl-x expression.

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“…[36][37][38][39] It has been known for some time that v-Src expression can increase the Stat-3 binding activity in certain cells 36 suggesting that there can be interactions between a vSrc induced downstream activity (possibly ERK) and STAT. Moreover, it is now recognized that the Raf kinase can be activated by IFN␥ and oncostatin M. [31][32][33][34]39 Interestingly, activation of Raf by these factors requires Jak and STATs, but this activation is Ras-independent, reducing the possibility of the involvement of an autocrine loop. 32,33,39 An unanswered question is whether the physical sites of Raf-1 activation by Jak are the same as those involved in activation by Src family kinases (Y340 and Y341)?…”

Section: Raf/mek/erk Activation By Interferons Abrogation Of Cytokinmentioning

confidence: 99%

“…INF␣/␤ and INF␥ can activate Raf-1 and B-Raf which will in turn activate MEK and the downstream ERK1 and ERK2 kinases. [31][32][33][34][35] Serine phosphorylation of STAT1 and STAT3 is required for these STATs to maximally transactivate gene expression. Dr Larner described how ERK is activated in response to interferons (IFN).…”

Section: Raf/mek/erk Activation By Interferons Abrogation Of Cytokinmentioning

confidence: 99%

Serine/threonine phosphorylation in cytokine signal transduction

et al. 2000

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Interferonγ Activation of Raf-1 Is Jak1-dependent and p21ras-independent

Cited by 73 publications

References 41 publications

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

Serine/threonine phosphorylation in cytokine signal transduction

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