Interferon alpha/beta signaling (Homo sapiens)

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23, 25, 37, 3925, 272422, 283815, 393921, 372, 9, 19, 363, 10, 2516, 23, 31, 427, 40, 435, 6, 8, 12-14, 18...11, 17273317, 411, 4, 21, 23, 30...33p-STAT2p-STAT1p-IFNAR1p-TYK2 ISGF3 p-STAT2p-STAT1 IFNA p-STAT2p-STAT1 p-STAT1 IFNAR1TYK2 IFNAR2JAK1STAT2 p-STAT2p-IFNAR1p-TYK2 p-IFNAR1p-TYK2 p-STAT2p-STAT1 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2STAT2 IFNAR1TYK2 IFN alpha/beta IFNA/BIFNAR2p-JAK1STAT2 p-STAT2STAT1p-IFNAR1p-TYK2 IFNA/BIFNAR2p-JAK1STAT2 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2p-STAT2STAT1 p-IFNAR1p-TYK2SOCS-1/SOCS-3 STAT2p-IFNAR1p-TYK2 ISGF3 bound to ISRE promotor elements IFN alpha/beta IFN alpha/beta IFN alpha/beta IFNA/BIFNAR2p-JAK1STAT2IFNAR1p-TYK2 IFNAR2JAK1STAT2 p-STAT2p-STAT1 IFNAR2p-JAK1STAT2 IFNAR1p-TYK2 IFNA IFNA/BIFNAR2JAK1STAT2 IFN alpha/beta p-STAT1 IFNAR2p-JAK1STAT2 IFNAR2p-JAK1STAT2 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2p-STAT2 IFNAR1TYK2 p-STAT1 IFNAR2cUBP43 IFNAR2p-JAK1STAT2 IFNA/BIFNAR2JAK1STAT2IFNAR1TYK2 IFNA p-STAT1 homodimer IFNA IFNA/BIFNAR2p-JAK1STAT2IFNAR1TYK2 IFNA IFNA p-STAT1 IFNAR2p-JAK1STAT2 IFNAR2p-JAK1STAT2 p-STAT2STAT1 SOCS-1 and SOCS-3 mitochondrionIFNA IFNAR2JAK1STAT2 STAT1 IFNA/BIFNAR2p-JAK1STAT2 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2p-STAT2p-STAT1 IFNAR2p-JAK1STAT2 nucleoplasmp-STAT2p-STAT1 endoplasmic reticulum lumencytosolIFN alpha/beta p-STAT1 p-STAT1p-STAT1 ISGF3 IFNA IFN alpha/beta IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2 IFN alpha/beta IFNAR2p-JAK1STAT2 IFN alpha/beta ISGF3 IFN alpha/beta IFNA IFNA p-TYK2p-IFNAR1SOCS-1/SOCS-3IFNA/BIFNAR2p-JAK1STAT2 IFNA/BIFNAR2p-JAK1STAT2 IFNA/BIFNAR2JAK1STAT2 IFNA17 IFNA1 IFNA21 IFNA8 p-Y1054,Y1055-TYK2 STAT2 PiIFNA17 IFNAR1 STAT2 SOCS1 IFNA10 IFNA10 ADARIFNA/BIFNAR2p-JAK1STAT2IFNAR1TYK2STAT1-1 p-TYK2p-IFNAR1SOCS-1/SOCS-3IFNA/BIFNAR2p-JAK1STAT2p-Y690-STAT2 IFNA21 IFNA21 IFNA14 EGR1IFNA2 IFNA2 PTPN11p-STAT2p-STAT1STAT2 RNASELH2OIRF 1-9IFNA4 IFNAR2-2 IFNA5 IFNAR2-2 IFNA2 PiIFNA5 IFNA5 IFNA6 p-Y-JAK1 JAK1 IFNB1 IFNB1 IFNA1 IFNA16 IFNA10 IRF9 p-Y-JAK1 p-Y690-STAT2 IFNA4 IFNA7 IFNAR2JAK1STAT2IFNA14 IFNB1 p-Y701-STAT1-1 IFI6IFITM1IFNA6 IFNB1 ATPSTAT2 p-Y701-STAT1-1 ADPISG20p-Y690-STAT2 IFNA1 IFNAR2-2 IFNA14 STAT2 IFNA10 IFNA8 IFNA6 p-Y-JAK1 IFNAR1 p-Y701-STAT1-2 p-Y-JAK1 IFNA21 IFNA5 IFNAR1 IFNB1 STAT2IFNA14 p-Y701-STAT1-2 IFNA8 IFITM2IFNA17 IFNA14 IFNA4 p-Y701-STAT1-2 IFNAR2-2STAT2 IFNB1 IFNA5 Class I MHC heavy chain IFNA21 TYK2 ISG15p-Y466,Y481-IFNAR1 IFNB1 IFNA6 IFIT3IFNA10 IFNAR1 IRF9 IFNA16 p-Y466,Y481-IFNAR1 PTPN6IFNA16 IFNAR2-2 ADPOAS proteinsSTAT2 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2p-STAT2SHP-2/SHP-1XAF1IFNAR2-2 p-Y701-STAT1-1 IFNA10 STAT2 IFNA14 p-Y701-STAT1-1 ATPIFNA5 IFNA16 IFNA16 IFNA10 IFNA5 IFNA8 IFNA5 IFNA4 Mx GTPasesIFITM3STAT1-1STAT2 IFNA21 IFNA7 JAK1 IFNAR2-2 IFNA6 STAT1-2 STAT2 IFNA5 p-Y-JAK1 JAK1 IFNA2 p-Y-JAK1 p-Y690-STAT2 IFNA21 IFIT2IFNA7 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2STAT2p-Y1054,Y1055-TYK2 IFNA16 IFNA7 ATPIFNA1 TYK2 IFNA/BIFNAR2JAK1STAT2IFNAR2-2 IFNA4 IFNA1 IRF9 IFNB1 p-Y1054,Y1055-TYK2 PTPN1IFNA16 IFNA6 p-Y466,Y481-IFNAR1 IFNA4 ATPATPIFNA7 IFNA6 IFNA4 IFNA17 IFNA2 p-Y690-STAT2 IFNA14 IFNA7 IFNB1 IFNA10 IFNA4 p-Y701-STAT1-2 IFNA7 IFNAR2-2 IP6K2IFNA2 IFNA1 IFNA16 IFNA21 IFNA4 IFNA21 PSMB8IFNA2 IRF9STAT2 IFNA7 p-Y701-STAT1-1 p-Y1054,Y1055-TYK2 IFNA21 SOCS-1 and SOCS-3IFNB1 IFNA17 IFNA17 p-Y-JAK1 IFNA2 IFNA8 p-STAT1 homodimerIFNA10 IFNA1 p-Y690-STAT2 IFNAR2-2 IFI27IFNA6 IFNA10 IFNA8 p-STAT1p-STAT1USP18 ISGF3 bound to ISRE promotor elementsp-Y701-STAT1-1 p-Y701-STAT1-2 p-Y1054,Y1055-TYK2 IFNA17 p-Y-JAK1 IFNA14 IFNA/BIFNAR2p-JAK1STAT2IFNAR1p-TYK2IFNA7 STAT1IFNA4 ISGF3USP18IFNA14 p-Y466,Y481-IFNAR1 p-Y1054,Y1055-TYK2 IFNAR2-2 IFIT1PiIFNA2 ADPIFN alpha/beta IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2p-STAT2STAT1IFNAR2cUBP43IFNA1 ISRE promoter elements in type I IFN-regulated genesIFNA8 IFNA8 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2IFNA8 IFNA1 H2OIFNA/BIFNAR2JAK1STAT2IFNAR1TYK2p-Y1054,Y1055-TYK2 p-Y690-STAT2 IFNA5 p-Y466,Y481-IFNAR1 IFNA2 IFNA16 IFNA6 IFNA6 IFNAR1TYK2IFNA17 GBP2IFNAR2-2 IFI35SOCS3 IFNA14 IFNA16 IFNA17 p-Y466,Y481-IFNAR1 H2OIFNA1 p-Y701-STAT1-1 IFNA8 ADPTYK2 ISGF3IFNAR2-2 IFNA17 IFNA/BIFNAR2p-JAK1STAT2p-IFNAR1p-TYK2p-STAT2p-STAT1IFNA7


Description

Type I interferons (IFNs) are composed of various genes including IFN alpha (IFNA), beta (IFNB), omega, epsilon, and kappa. In humans the IFNA genes are composed of more than 13 subfamily genes, whereas there is only one IFNB gene. The large family of IFNA/B proteins all bind to a single receptor which is composed of two distinct chains: IFNAR1 and IFNAR2. The IFNA/B stimulation of the IFNA receptor complex leads to the formation of two transcriptional activator complexes: IFNA-activated-factor (AAF), which is a homodimer of STAT1 and IFN-stimulated gene factor 3 (ISGF3), which comprises STAT1, STAT2 and a member of the IRF family, IRF9/P48. AAF mediates activation of the IRF-1 gene by binding to GAS (IFNG-activated site), whereas ISGF3 activates several IFN-inducible genes including IRF3 and IRF7. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=909733

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
114797view16:29, 25 January 2021ReactomeTeamReactome version 75
113240view11:30, 2 November 2020ReactomeTeamReactome version 74
112460view15:41, 9 October 2020ReactomeTeamReactome version 73
101367view11:25, 1 November 2018ReactomeTeamreactome version 66
100905view21:00, 31 October 2018ReactomeTeamreactome version 65
100446view19:35, 31 October 2018ReactomeTeamreactome version 64
99995view16:19, 31 October 2018ReactomeTeamreactome version 63
99549view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99182view12:42, 31 October 2018ReactomeTeamreactome version 62
93744view13:33, 16 August 2017ReactomeTeamreactome version 61
93258view11:18, 9 August 2017ReactomeTeamreactome version 61
86337view09:15, 11 July 2016ReactomeTeamreactome version 56
83224view10:25, 18 November 2015ReactomeTeamVersion54
81620view13:09, 21 August 2015ReactomeTeamVersion53
77078view08:37, 17 July 2014ReactomeTeamFixed remaining interactions
76783view12:14, 16 July 2014ReactomeTeamFixed remaining interactions
76106view10:17, 11 June 2014ReactomeTeamRe-fixing comment source
75818view11:37, 10 June 2014ReactomeTeamReactome 48 Update
75168view14:11, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74815view08:54, 30 April 2014ReactomeTeamReactome46
44864view09:57, 6 October 2011MartijnVanIerselOntology Term : 'immune response pathway' added !
42055view21:53, 4 March 2011MaintBotAutomatic update
39861view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADARProteinP55265 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Class I MHC heavy chain ProteinREACT_26784 (Reactome)
EGR1ProteinP18146 (Uniprot-TrEMBL)
GBP2ProteinP32456 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
IFI27ProteinP40305 (Uniprot-TrEMBL)
IFI35ProteinP80217 (Uniprot-TrEMBL)
IFI6ProteinP09912 (Uniprot-TrEMBL)
IFIT1ProteinP09914 (Uniprot-TrEMBL)
IFIT2ProteinP09913 (Uniprot-TrEMBL)
IFIT3ProteinO14879 (Uniprot-TrEMBL)
IFITM1ProteinP13164 (Uniprot-TrEMBL)
IFITM2ProteinQ01629 (Uniprot-TrEMBL)
IFITM3ProteinQ01628 (Uniprot-TrEMBL)
IFN alpha/beta ProteinREACT_26595 (Reactome)
IFNA/B

IFNAR2 JAK1 STAT2 IFNAR1

TYK2		ComplexREACT_25725 (Reactome)
IFNA/B

IFNAR2 JAK1

STAT2		ComplexREACT_26015 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

TYK2		ComplexREACT_26140 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

p-TYK2		ComplexREACT_26001 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

STAT2		ComplexREACT_25990 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2 p-STAT2

STAT1		ComplexREACT_26740 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2 p-STAT2

p-STAT1		ComplexREACT_26770 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

p-STAT2		ComplexREACT_26908 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1

p-TYK2		ComplexREACT_26083 (Reactome)
IFNA1 ProteinP01562 (Uniprot-TrEMBL)
IFNA10 ProteinP01566 (Uniprot-TrEMBL)
IFNA14 ProteinP01570 (Uniprot-TrEMBL)
IFNA16 ProteinP05015 (Uniprot-TrEMBL)
IFNA17 ProteinP01571 (Uniprot-TrEMBL)
IFNA2 ProteinP01563 (Uniprot-TrEMBL)
IFNA21 ProteinP01568 (Uniprot-TrEMBL)
IFNA4 ProteinP05014 (Uniprot-TrEMBL)
IFNA5 ProteinP01569 (Uniprot-TrEMBL)
IFNA6 ProteinP05013 (Uniprot-TrEMBL)
IFNA7 ProteinP01567 (Uniprot-TrEMBL)
IFNA8 ProteinP32881 (Uniprot-TrEMBL)
IFNAR1 TYK2ComplexREACT_25562 (Reactome)
IFNAR1 ProteinP17181 (Uniprot-TrEMBL)
IFNAR2

JAK1

STAT2		ComplexREACT_25438 (Reactome)
IFNAR2-2 ProteinP48551-2 (Uniprot-TrEMBL)
IFNAR2-2ProteinP48551-2 (Uniprot-TrEMBL)
IFNAR2c UBP43ComplexREACT_26598 (Reactome)
IFNB1 ProteinP01574 (Uniprot-TrEMBL)
IP6K2ProteinQ9UHH9 (Uniprot-TrEMBL)
IRF 1-9ProteinREACT_26465 (Reactome)
IRF9 ProteinQ00978 (Uniprot-TrEMBL)
IRF9ProteinQ00978 (Uniprot-TrEMBL)
ISG15ProteinP05161 (Uniprot-TrEMBL)
ISG20ProteinQ96AZ6 (Uniprot-TrEMBL)
ISGF3 bound to ISRE promotor elementsComplexREACT_25455 (Reactome)
ISGF3ComplexREACT_25406 (Reactome)
ISGF3ComplexREACT_25831 (Reactome)
ISRE promoter elements in type I IFN-regulated genesREACT_26432 (Reactome)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
Mx GTPasesProteinREACT_25553 (Reactome)
OAS proteinsProteinREACT_26755 (Reactome)
PSMB8ProteinP28062 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RNASELProteinQ05823 (Uniprot-TrEMBL)
SHP-2/SHP-1ProteinREACT_20250 (Reactome)
SOCS-1 and SOCS-3ProteinREACT_25587 (Reactome)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS3 ProteinO14543 (Uniprot-TrEMBL)
STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
STAT1-1ProteinP42224-1 (Uniprot-TrEMBL)
STAT1-2 ProteinP42224-2 (Uniprot-TrEMBL)
STAT1ProteinREACT_17621 (Reactome)
STAT2 ProteinP52630 (Uniprot-TrEMBL)
STAT2ProteinP52630 (Uniprot-TrEMBL)
TYK2 ProteinP29597 (Uniprot-TrEMBL)
USP18 ProteinQ9UMW8 (Uniprot-TrEMBL)
USP18ProteinQ9UMW8 (Uniprot-TrEMBL)
XAF1ProteinQ6GPH4 (Uniprot-TrEMBL)
p-STAT1 p-STAT1ComplexREACT_26749 (Reactome)
p-STAT1 homodimerComplexREACT_26275 (Reactome)
p-STAT2 p-STAT1ComplexREACT_27063 (Reactome)
p-TYK2

p-IFNAR1 SOCS-1/SOCS-3 IFNA/B IFNAR2 p-JAK1

STAT2		ComplexREACT_26646 (Reactome)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y1054,Y1055-TYK2 ProteinP29597 (Uniprot-TrEMBL)
p-Y466,Y481-IFNAR1 ProteinP17181 (Uniprot-TrEMBL)
p-Y690-STAT2 ProteinP52630 (Uniprot-TrEMBL)
p-Y701-STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
p-Y701-STAT1-2 ProteinP42224-2 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADARArrowREACT_25192 (Reactome)
ADPArrowREACT_25105 (Reactome)
ADPArrowREACT_25291 (Reactome)
ADPArrowREACT_25383 (Reactome)
ADPArrowREACT_25401 (Reactome)
ATPREACT_25017 (Reactome)
ATPREACT_25105 (Reactome)
ATPREACT_25291 (Reactome)
ATPREACT_25383 (Reactome)
ATPREACT_25401 (Reactome)
Class I MHC heavy chain ArrowREACT_25192 (Reactome)
EGR1ArrowREACT_25192 (Reactome)
GBP2ArrowREACT_25192 (Reactome)
H2OREACT_24939 (Reactome)
H2OREACT_25289 (Reactome)
H2OREACT_25329 (Reactome)
IFI27ArrowREACT_25192 (Reactome)
IFI35ArrowREACT_25192 (Reactome)
IFI6ArrowREACT_25192 (Reactome)
IFIT1ArrowREACT_25192 (Reactome)
IFIT2ArrowREACT_25192 (Reactome)
IFIT3ArrowREACT_25192 (Reactome)
IFITM1ArrowREACT_25192 (Reactome)
IFITM2ArrowREACT_25192 (Reactome)
IFITM3ArrowREACT_25192 (Reactome)
IFN alpha/beta REACT_25100 (Reactome)
IFNA/B

IFNAR2 JAK1 STAT2 IFNAR1

TYK2		ArrowREACT_25289 (Reactome)
IFNA/B

IFNAR2 JAK1 STAT2 IFNAR1

TYK2		REACT_25065 (Reactome)
IFNA/B

IFNAR2 JAK1 STAT2 IFNAR1

TYK2		REACT_25401 (Reactome)
IFNA/B

IFNAR2 JAK1 STAT2 IFNAR1

TYK2		mim-catalysisREACT_25401 (Reactome)
IFNA/B

IFNAR2 JAK1

STAT2		REACT_25206 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

TYK2		ArrowREACT_25329 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

TYK2		REACT_25289 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

p-TYK2		ArrowREACT_25401 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

p-TYK2		REACT_25329 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

p-TYK2		REACT_25383 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 IFNAR1

p-TYK2		mim-catalysisREACT_25383 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

STAT2		REACT_25291 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

STAT2		mim-catalysisREACT_25291 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2 p-STAT2

STAT1		ArrowREACT_24939 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2 p-STAT2

p-STAT1		REACT_24939 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

p-STAT2		ArrowREACT_25291 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

p-STAT2		REACT_25017 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

p-STAT2		mim-catalysisREACT_25017 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1 p-TYK2

p-STAT2		mim-catalysisREACT_25105 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1

p-TYK2		ArrowREACT_25021 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1

p-TYK2		ArrowREACT_25383 (Reactome)
IFNA/B

IFNAR2 p-JAK1 STAT2 p-IFNAR1

p-TYK2		REACT_25238 (Reactome)
IFNAR1 TYK2REACT_25206 (Reactome)
IFNAR2

JAK1

STAT2		REACT_25100 (Reactome)
IFNAR2-2REACT_24958 (Reactome)
IP6K2ArrowREACT_25192 (Reactome)
IRF 1-9ArrowREACT_25192 (Reactome)
IRF9REACT_25284 (Reactome)
ISG15ArrowREACT_25192 (Reactome)
ISG20ArrowREACT_25192 (Reactome)
ISGF3 bound to ISRE promotor elementsArrowREACT_25192 (Reactome)
ISGF3REACT_24942 (Reactome)
ISRE promoter elements in type I IFN-regulated genesREACT_24942 (Reactome)
Mx GTPasesArrowREACT_25192 (Reactome)
OAS proteinsArrowREACT_25192 (Reactome)
PSMB8ArrowREACT_25192 (Reactome)
PTPN11mim-catalysisREACT_24939 (Reactome)
PTPN1mim-catalysisREACT_25329 (Reactome)
PTPN6mim-catalysisREACT_25289 (Reactome)
PiArrowREACT_24939 (Reactome)
PiArrowREACT_25289 (Reactome)
PiArrowREACT_25329 (Reactome)
REACT_24939 (Reactome) SHP2 negatively regulates the IFN-induced JAK-STAT pathway by dephosphorylating STAT1 on Y701.
REACT_24942 (Reactome) Effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). These ISGs are mainly implicated in anti-viral, anti-angiogenic, immunomodulatory, cell cycle inhibitory effects and apoptotic functions. All IFNA/B-stimulated genes have a conserved region of about 15bp in their promoter called the Interferon Stimulation Response Element (ISRE). The transcription factor ISGF3 binds to this ISRE and induce the transcription of these genes by IFN.
REACT_24958 (Reactome) UBP43, a type I IFN-inducible cysteine protease acts as a negative regulator of type I IFN signaling. UBP43 binds directly to IFNAR2 and blocks JAK-receptor interaction leading to inhibition of downstream phosphorylation and other signaling events.
REACT_25017 (Reactome) Phosphotyrosine on STAT2 acts as docking site for STAT1 molecules. STAT1 binds to phosphorylated STAT2 and this is followed by STAT1 phosphorylation on tyrosine residue 701 (Y701) and is followed by p-STAT2:p-STAT1 heterodimer formation and nuclear translocation.
REACT_25021 (Reactome) The phosphorylated STAT2:STAT1 heterodimers thus formed disassociate from the IFNAR1 subunit and translocates to the nucleus.
REACT_25065 (Reactome) SOCS1/3 are the major negative regulators of IFNA/B signaling. They inhibit JAKs catalytic activity directly through their kinase inhibitory region (KIR) and turn off downstream IFNA/B signaling. SOCS1 may also prevent IFN signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway.
REACT_25100 (Reactome) The ligand IFNalpha/beta (IFNA/B), interacts independently with the two interferon receptor subunits. Based on detailed binding studies with the extracellular domains of the receptor subunits tethered onto solid-supported membranes, a two-step binding mechanism was experimentally confirmed, where the ligand binds first to one of the receptor subunits and then recruits the second subunit (Gavutis et al. 2005). The efficiency of recruitment of the IFNA receptor subunits by the IFN ligand depends on the absolute and relative concentration of the receptor subunits.
IFNAR2 chain constitutively associates with JAK1 kinase in its cytoplasmic domain. In addition IFNAR2 also binds STAT2 in a constitutive manner and this interaction is biochemically different from the interaction of STAT2 with phosphorylated IFNAR1. Although this interaction facilitates the recruitment of STAT2 to the receptors, the biological significance of this constitutive STAT2 interaction to IFNAR2 remains unclear (Nguyen et al, 2002). IFNAR2 not only associates with STAT2, but also with STAT1 and this binding of STAT1 to IFNAR2 depends on the presence of STAT2 but not vice versa.
IFNA/B may first bind to the high-affinity subunit IFNAR2 and subsequently recruit IFNAR1 in a transient fashion (Lamken et al. 2004). Different type I IFNs interact differently with the two IFNA receptor (IFNAR) subunits, IFNB generates a more stable signaling complex than IFNA subtypes. The interaction between IFNalpha2 (IFNA2) and IFNAR2 has an affinity in the nM range, whereas the affinity of the interaction with INFB is about tenfold tighter.
REACT_25105 (Reactome) Under certain conditions type I IFNs, IFNA/B are able to activate genes through a second STAT-based signaling cascade enabling the formation of p-STAT1:p-STAT1 homodimers called IFNA-activated-factor (AAF).
REACT_25169 (Reactome) The resultant ISGF3 trimeric complex then migrates to the nucleus and binds to interferon-stimulated response elements (ISREs). IRF9 is the DNA binding part of this ISGF3 complex. These ISREs are present in the promoters of a subset of ISGs (interferon stimulated genes), such as promyelocytic leukemia (PML), ISG15 ubiquitin-like modifier (ISG15), interferon-induced protein with tetratricopeptide repeats 2 (ISG54) and interferon alpha-inducible protein 6 (IFI6) to elicit an antiviral response.
REACT_25192 (Reactome) Around 300 IFN-induced genes have been identified from different oligonucleotide microarray studies in melanoma (WM9) and fibrosarcoma (HT1080) cell lines as well as from human dendritic cells treated with IFN. Only the proteins which are well studied and their function characterized are represented here.
REACT_25206 (Reactome) The extracellular domain of IFNAR1 is atypical, consisting of a tandem array of four FNIII domains and the first three N-terminal FNIII domains are involved in ligand recognition. IFNAR1 is recruited to the binary complex (IFNA/B:IFNAR2) on the membrane to form the ternary complex (IFNAR2:IFNA/B:IFNAR1). TYK2 kinase is pre-associated with IFNAR1 and JAK1 with IFNAR2. The binding of IFNA/B to IFNA receptors brings these JAK kinase together, allowing cross-phosphorylation and kinase activation.
REACT_25238 (Reactome) Phosphorylated tyrosine residue 466 on IFNAR1 acts as a docking site for STAT2. Latent STAT2 is recruited to this phosphotyrosine residue via its SH2 domain.
REACT_25256 (Reactome) IFNA-activated-factor (AAF) translocates to nucleus and then promotes the expression of a distinct set of gamma activated sequence (GAS)-driven genes like IRF1. IRF1, in turn, induces the transcription of ISG15, ISG54 and IFI6 genes. This second pathway of STAT1 homodimer formation is primarily activated by IFNG and is likely to account for some of the functional overlap between type I and type II IFNs.
REACT_25284 (Reactome) The phosphorylated STAT2:STAT1 heterodimer associates with interferon-regulating factor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex.
REACT_25289 (Reactome) SHP1 directly associates with and dephosphorylates JAK1/2.
REACT_25291 (Reactome) STAT2 recruited to the IFNAR1 subunit then becomes tyrosine phosphorylated on residue 690 by TYK2 kinase. This phosphotyrosine provides a docking site for recruitment of STAT1 to IFNAR1, which is then tyrosine phosphorylated and activated.
REACT_25329 (Reactome) TYK2 bears the substrate recognition motif for PTP1B, and on IFN stimulation PTP1B interacts with and dephosphorylates TYK2.
REACT_25383 (Reactome) TYK2 functions as part of a receptor complex to trigger intracellular signaling in response to IFNA/B. TYK2 bound to IFNAR1 subunit is activated in response to IFNA/B treatment and this in turn phosphorylates two tyrosine residues Y466 and Y481 in the juxta-membrane region of IFNAR1.
REACT_25401 (Reactome) The two chains IFNAR1 and IFNAR2 are pre-associated with the JAK kinases TYK2 and JAK1, respectively. Receptor heterodimerization brings these JAK kinases into close proximity and they are activated by reciprocal trans-phosphorylation. Tyr-1054 and Tyr-1055 within the activation loop of TYK2 sub-domain VII are critical for TYK2 activation. For JAK1 two tyrosine residues with in the KEYY motif (Tyr 1034 and Tyr 1035) of the kinase domain are thought to be transphosphorylated.
RNASELArrowREACT_25192 (Reactome)
SHP-2/SHP-1TBarREACT_25017 (Reactome)
SOCS-1 and SOCS-3REACT_25065 (Reactome)
STAT1-1REACT_25105 (Reactome)
STAT1REACT_25017 (Reactome)
STAT2REACT_25238 (Reactome)
USP18REACT_24958 (Reactome)
XAF1ArrowREACT_25192 (Reactome)
p-STAT1 homodimerArrowREACT_25105 (Reactome)
p-STAT2 p-STAT1ArrowREACT_25021 (Reactome)
p-STAT2 p-STAT1REACT_25284 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1835"
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