Role of interferon alpha/beta receptor chain 1 in the structure and transmembrane signaling of the interferon alpha/beta receptor complex.

Constantinescu, Stefan N.; Croze, Ed; Wang, Chiang; Murti, Aruna; Basu, Leela; Mullersman, Jerald E.; Pfeffer, Lawrence M.

doi:10.1073/pnas.91.20.9602

Cited by 99 publications

(99 citation statements)

References 33 publications

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“…The IFNAR-1 chain plays a critical role in the function of the IFN␣͞␤ receptor. IFNAR-1 acts as a species-specific transducer for type 1 IFN action undergoing rapid IFN-dependent tyrosine phosphorylation, and its knockout in mice results in the loss of the antiviral response to type 1 IFNs (28,32,36,37). We have previously identified a conserved motif within the intracellular domain of IFNAR-1, which is required for the IFN-dependent activation of STAT3 and phosphatidyinositol 3-kinase (PI-3K) (17,38).…”

Section: Discussionmentioning

confidence: 99%

“…Type 1 IFNs bind to a ubiquitously expressed cell-surface receptor, composed of the IFNAR-1 and IFNAR-2 subunits (2,4,30,31). Whereas IFNAR-2 is the ligand-binding subunit, IFNAR-1 acts as a species-specific transducer for the actions of type 1 IFN (28,32). These receptor subunits have no inherent enzyme activity, but generate cytoplasmic signals in combination with the nonreceptor Janus protein tyrosine kinases and STAT proteins.…”

Section: Discussionmentioning

confidence: 99%

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IFNα/β promotes cell survival by activating NF-κB

Yang

Murti

Pfeffer

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

153

121

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IFNα/β promotes cell survival by activating NF-κB

Yang

Murti

Pfeffer

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

153

121

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“…The receptor consists of two subunits IFNAR1 and IFNAR2 (reviewed in [1]). IFNAR1 plays a key role in all aspects of IFNα-mediated effects in vitro and in vivo [2][3][4], and anti-proliferative activity of Type I IFN variants directly correlates with affinity of their binding to IFNAR1 [5].…”

Section: Introductionmentioning

confidence: 99%

“…Down regulation and degradation of IFNAR1 in response IFNα treatment is a pivotal mechanism limiting the extent of cellular responses to IFNα [6,7]. Turnover of IFNAR1 requires its ubiquitination by the SCF β-Trcp/HOS E3 ubiquitin ligase [8], which recognizes the conserved phosphorylated 534 DSGNYS destruction motif [9].…”

Section: Introductionmentioning

confidence: 99%

Ligand-independent pathway that controls stability of interferon alpha receptor

Liu

Plotnikov

Banerjee

et al. 2008

Biochemical and Biophysical Research Communications

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SUMMARYLigand-specific negative regulation of cytokine-induced signaling relies on down regulation of the cytokine receptors. Down regulation of the IFNAR1 sub-unit of the Type I interferon (IFN) receptor proceeds via lysosomal receptor proteolysis, which is triggered by ubiquitination that depends on IFNAR1 serine phosphorylation. While IFN-inducible phosphorylation, ubiquitination and degradation requires the catalytic activity of the Tyk2 Janus kinase, here we found the ligand-and Tyk2-independent pathway that promotes IFNAR1 phosphorylation, ubiquitination, and degradation when IFNAR1 is expressed at high levels. A major cellular kinase activity that is responsible for IFNAR1 phosphorylation in vitro does not depend on either ligand or Tyk2 activity. Inhibition of ligand-independent IFNAR1 degradation suppresses cell proliferation. We discuss the signaling events that might lead to ubiquitination and degradation of IFNAR1 via ligand-dependent and independent pathways and their potential physiologic significance.

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“…The ␣ subunit interacts with Tyk2 (4,19,20) while the cytoplasmic domain of the ␤ L contains a docking site for Jak1 (18). Binding of type I IFNs to their receptor triggers rapid tyrosine phosphorylation of Tyk2 and Jak1 kinases, type I IFN-R subunits (21)(22)(23)(24)(25), and Stat factors (reviewed in Refs. 26 -28).…”

mentioning

confidence: 99%

Identification of a Domain in the β Subunit of the Type I Interferon (IFN) Receptor That Exhibits a Negative Regulatory Effect in the Growth Inhibitory Action of Type I IFNs

Platanias

Domanski

Nadeau

et al. 1998

Journal of Biological Chemistry

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Expression of human ␣ and long form of the ␤ (␤ L ) subunits of type I interferon receptor (IFN-R) in mouse cells is sufficient to activate the Jak-Stat pathway and to elicit an antiviral state in response to human IFN␣2 and IFN␤. We demonstrate herein, however, that these cells respond to the antiproliferative effects of murine IFN␣␤ but not human type I IFNs. These results suggest that an unknown species-specific component is required for the antiproliferative effect of human type I IFNs. The absence of this component can be complemented by expressing the human ␤ L chain truncated at amino acid 346. Thus, the distal region of ␤ L appears to function as a negative regulator of the growth inhibitory effects of type I IFNs. Further studies looking for possible targets of the ␤ L regulatory domain demonstrated that this region associates with a tyrosine phosphatase. These results suggest that a protein associated with the negative regulatory domain of ␤ L , likely a tyrosine phosphatase, plays a role in regulating the growth inhibitory effects of human type I IFNs.The most prominent effects of type I interferons (IFN) 1 are the antiviral and antiproliferative actions (1). These effects are mediated through binding to the type I interferon receptor (IFN-R or IFN␣R), which is composed of two subunits termed ␣, or IFNAR1, and ␤, or IFNAR2 (2-10). The genes encoding the different subunits of the type I IFN-R are clustered in the q22.1 region of human chromosome 21 (6,7,(11)(12)(13)(14)(15)(16)). This region also harbors an orphan class II cytokine receptor, the CRFB-4 gene, which is encoded on human chromosome 21 between the genes for the ␤ chain of the IFN␣R and the ␤ subunit of the IFN␥R (10, 17). Expression of the human ␣ and long form of the ␤ chain (␤ L ) subunits in mouse L-929 cells fully reconstitutes the activation of the Jak-Stat pathway and the induction of an antiviral state in response to HuIFN␣2 and HuIFN␤ (9). Furthermore, only the first 82 amino acids of the cytoplasmic domain of the ␤ L chain are required to activate the Jak-Stat pathway and induce the antiviral effect in response to IFN␣2 (18).The ␣ and ␤ subunits of the type I IFN-R associate with protein tyrosine kinases of the Jak family (4,8,18). The ␣ subunit interacts with Tyk2 (4,19,20) while the cytoplasmic domain of the ␤ L contains a docking site for Jak1 (18). Binding of type I IFNs to their receptor triggers rapid tyrosine phosphorylation of Tyk2 and Jak1 kinases, type I IFN-R subunits (21-25), and Stat factors (reviewed in Refs. 26 -28). Regulation of tyrosine kinase activity is mediated in most cytokine systems by protein tyrosine phosphatases (PTPs). For example, SHP1 (also named SHP, SHPTP1, HCP; PTP1C, Ref. 29), a predominantly hematopoietic tyrosine phosphatase that regulates the activity of the erythropoietin and IL-3 systems (30 -35), has also been implicated in IFN␣ signaling in hematopoietic cells (36,37). However, the role of SHP1 in other cell types is not clear since this PTP is mainly expressed in hematopoietic cells, wher...

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Role of interferon alpha/beta receptor chain 1 in the structure and transmembrane signaling of the interferon alpha/beta receptor complex.

Cited by 99 publications

References 33 publications

IFNα/β promotes cell survival by activating NF-κB

IFNα/β promotes cell survival by activating NF-κB

Ligand-independent pathway that controls stability of interferon alpha receptor

Identification of a Domain in the β Subunit of the Type I Interferon (IFN) Receptor That Exhibits a Negative Regulatory Effect in the Growth Inhibitory Action of Type I IFNs

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