Ligand-independent pathway that controls stability of interferon alpha receptor

Liu, Jianghuai; Plotnikov, A.N.; Banerjee, Anamika; Kumar, Krishna; Ragimbeau, Josiane; Marijanovic, Zrinka; Baker, Darren P.; Pellegrini, Sandra; Fuchs, Serge Y.

doi:10.1016/j.bbrc.2007.12.137

Cited by 45 publications

(75 citation statements)

References 25 publications

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“…34,35 This phosphorylation can be induced by IFN␣ in a manner that depends on activity of JAK1 and TYK2 22,36 and downstream activation of PKD2. 37 Alternatively, basal phosphorylation of Ser535 by CK1␣ 38 is shown to be augmented by a priming site (Ser532) phosphorylation, which can be promoted by signaling stimulated by inducers of unfolded protein responses such as thapsigargin.…”

Section: Resultsmentioning

confidence: 99%

“…26 Bcr-abl is capable of activating Janus kinases 39 whose catalytic activity is required for Ser535 phosphorylation and IFNAR1 degradation induced by IFN␣. 36 Although slightly attenuated, a noticeable down-regulation of IFNAR1 was seen in Bcr-ablexpressing KR cells ( Figure 4C) that express kinase-dead TYK2 and are deficient in IFNAR1 degradation induced by IFN␣. 22 Furthermore, only a partial attenuation of IFNAR1 downregulation in Bcr-abl-expressing HeLa cells was achieved by treating these cells with JAK inhibitor 1 ( Figure 4D).…”

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confidence: 97%

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Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Bhattacharya¹,

Zheng²,

Tzimas³

et al. 2011

Blood

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IntroductionPatients with chronic myeloid leukemia (CML) harbor a specific translocation t(9;22)(q34;q11), the Philadelphia chromosome, resulting in the expression of a constitutively active protein tyrosine kinase Bcr-abl that is essential for the hematopoietic cell transformation. 1 This kinase exerts its oncogenic function by activating a cascade of intracellular signaling pathways that lead to increased cell survival and proliferation and limited dependence on growth factors. Among these pathways are those that mediate activation of PI3K-Akt, MAPK, and protein kinase (PK)C/PKD signaling cascades that generally stimulate cell proliferation and survival. 2,3 The Bcr-abl inhibitor imatinib mesylate (IM) has replaced interferon IFN␣ as the standard of care for patients with newly diagnosed chronic myeloid leukemia (CML) because of higher response frequency, substantially superior molecular and cytogenetic responses, lesser toxicity, and better survival. [4][5][6][7] Yet, although rapidly killing differentiated CML cells, IM is less efficient against more primitive leukemic stem cells and early progenitor cells. 8,9 Thus, patients receiving IM are not cured and require life-long treatment that is often compromised by resistance to IM because of mutations in Bcr-abl tyrosine kinase. 7,10 The ability of the second and third generation of tyrosine kinase inhibitors (TKIs; eg, dasatinib that might be active against mutant kinases) to eradicate quiescent early CML progenitors remains to be determined. 11 It is plausible that a combination of Bcr-abl inhibitors and the agents targeting the leukemic stem cell population might be required to eradicate the disease in CML patients.Recent evidence suggests that leukemic stem cells might undergo terminal differentiation in response to IFN␣, 12 a cytokine known to produce a curative effect in a small subset of patients (reviewed in Kujawski and Talpaz 13 ). Although these results, along with reports on several cases of successful treatment with IFN␣ after a course of IM (or vice versa), 14,15 provide new enthusiasm for the reintroduction of IFN␣ into the management of CML, 13 the molecular mechanisms that underlie the rationale for combining Bcr-abl inhibitors and IFN␣ remain to be delineated. Cellular responses to IFN␣ are mediated by the cell surface type I IFN receptor that consists of the interferon-␣/␤ receptor (IFNAR)1 and IFNAR2 chains. Ligand-stimulated dimerization of these chains leads to the activation of Janus kinase (JAK) family members JAK1 and TYK2. JAK1 and TYK2 phosphorylate signal transducers and activators of transcription (STAT) family proteins at specific tyrosine residues. Tyrosine phosphorylation of STAT1 and STAT2 along with subsequent recruitment of p48/IRF9 leads to the formation of a potent transcription factor that transactivates IFN-stimulated genes and contribute to the antiproliferative effects of IFN␣ (for reviews, see [16][17][18][19] ).A better understanding of molecular interactions between IFN␣-and Bcr-abl-induced signaling pathways is requ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 97%

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Bhattacharya¹,

Zheng²,

Tzimas³

et al. 2011

Blood

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“…The accumulating evidence shows that besides the well-characterized ligand-induced pathways, there are ligand-independent pathways of receptor degradation. However, the molecular mechanisms that maintain the basal levels of receptors, and are underlying ligand-independent receptor degradation are not well understood [46,47].…”

Section: Discussionmentioning

confidence: 99%

E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors

Jing

Infante

Nachtman

et al. 2008

Experimental Hematology

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Objective-FLRF (Rnf41) gene was identified through screening of subtracted cDNA libraries form murine hematopoietic stem cells and progenitors. Subsequent work has revealed that FLRF acts as E3 ubiquitin ligase, and that it regulates steady-state levels of neuregulin receptor ErbB3, and participates in degradation of IAP protein BRUCE and parkin. The objective of this study was to start exploring the role of FLRF during hematopoiesis.Methods-FLRF was over-expressed in a murine multipotent hematopoietic progenitor cell line EML, which can differentiate into almost all blood cell lineages, and in pro-B progenitor cell line BaF3. The impact of FLRF over-expression on EML cell differentiation into myelo-erythroid lineages was studied using hematopoietic colony-forming assays. The interaction of FLRF with cytokine receptors and receptor levels in control cells and EML and BaF3 cells over-expressing FLRF were examined with Western and immunoprecipitation.Results-Remarkably, over-expression of FLRF significantly attenuated erythroid and myeloid differentiation of EML cells in response to cytokines Epo and IL-3, and retinoic acid (RA), and resulted in significant and constitutive decrease of steady-state levels of IL-3, Epo and RA receptor RARα in EML and BaF3 cells. Immunoprecipitation has revealed that FLRF interacts with IL-3, Epo and RARα receptors in EML and BaF3 cells, and that FLRF-mediated down-regulation of these receptors is ligand binding-independent.Conclusions-The results of this study have revealed new FLRF-mediated pathway for ligandindependent receptor level regulation, and support the notion that through maintaining basal levels of cytokine receptors, FLRF is involved in the control of hematopoietic progenitor cell differentiation into myelo-erythroid lineages.

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“…Importantly, phosphorylation of IFNAR1 on Ser-535 in these cells was not robustly stimulated by IFN␣ treatment (Fig. 1A) (14,15).…”

Section: Resultsmentioning

confidence: 99%

“…This ubiquitination is facilitated by the SCF ␤Trcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its phosphorylation on specific Ser residues within a defined degron ( 534 DSGNYS) (11,12). Stimulation of this phosphorylation in cells exposed to IFN␣/␤ appears to play a key role in subsequent recruitment of ␤Trcp and stimulation of IFNAR1 ubiquitination and degradation (11,13) in a manner that requires catalytic activity of TYK2 (14,15).…”

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confidence: 99%

Tyrosine Phosphorylation of Protein Kinase D2 Mediates Ligand-inducible Elimination of the Type 1 Interferon Receptor

Zheng

Qian

Baker

et al. 2011

Journal of Biological Chemistry

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Type 1 interferons (including IFN␣/␤) activate their cell surface receptor to induce the intracellular signal transduction pathways that play an important role in host defenses against infectious agents and tumors. The extent of cellular responses to IFN␣ is limited by several important mechanisms including the ligand-stimulated and specific serine phosphorylation-dependent degradation of the IFNAR1 chain of Type 1 IFN receptor. Previous studies revealed that acceleration of IFNAR1 degradation upon IFN stimulation requires activities of tyrosine kinase TYK2 and serine/threonine protein kinase D2 (PKD2), whose recruitment to IFNAR1 is also induced by the ligand. Here we report that activation of PKD2 by IFN␣ (but not its recruitment to the receptor) depends on TYK2 catalytic activity. PKD2 undergoes IFN␣-inducible tyrosine phosphorylation on specific phospho-acceptor site (Tyr-438) within the plekstrin homology domain. Activated TYK2 is capable of facilitating this phosphorylation in vitro. Tyrosine phosphorylation of PKD2 is required for IFN␣-stimulated activation of this kinase as well as for efficient serine phosphorylation and degradation of IFNAR1 and ensuing restriction of the extent of cellular responses to IFN␣.Type 1 interferons (IFNs) play a critical role in modulating the immune responses against many pathogens and directly mounting the anti-viral defenses (for review, see Refs. 1-4). A family of these cytokines (including IFN␤ and diverse species of IFN␣) elicit the responses through the cognate Type 1 IFN receptor on the cell surface (5-7). Interaction of IFNAR1 2 and IFNAR2c chains of this receptor with the ligands triggers the signal transduction pathway that involves activation of the Janus kinases, JAK (TYK2 and JAK1) and subsequent tyrosine phosphorylation and ensuing activation of signal transducers and activators of transcription (STAT1 and STAT2). Transcriptionally active STAT1/2 further associate with IRF3, translocate to the nucleus and interact with IFN-stimulated response elements (ISRE) to induce de novo expression of the IFN-stimulated genes. Protein products of these mediate immunomodulatory and anti-viral responses as well as inhibit proliferation and survival of cells exposed to Type 1 IFN (for review, see Refs. 1-4).To alleviate these detrimental effects of Type 1 IFN, cells evolved to develop the mechanisms that limit the magnitude and duration of their responses to these cytokines. For example, some of the IFN-stimulated genes encode the proteins that may interfere with the recruitment of JAK to IFNAR chains (8). Additional modes of negative regulation that is commonly shared between most of cytokines-induced JAK-STAT pathways include inhibition of JAK activity/stimulation of JAK degradation by SOCS proteins, inhibition of tyrosine phosphorylation by phosphatases, and inhibition of STAT-induced transcription by PIAS (for review, see Refs. 6, 9). In addition to these modes of negative regulation, which occur in cells that have already executed the IFN-induced programs of signal tra...

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Ligand-independent pathway that controls stability of interferon alpha receptor

Cited by 45 publications

References 25 publications

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors

Tyrosine Phosphorylation of Protein Kinase D2 Mediates Ligand-inducible Elimination of the Type 1 Interferon Receptor

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