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Biomap#31

Title: Interferon alpha (IFN alpha) pathway
 
Legend: Interferon alpha (IFN alpha) belongs to the type I IFN family together with IFN beta, omega, epsilon and kappa. These cytokines signal through a hetrodimeric receptor complex composed of IFN alpha receptor 1 (IFNAR1) and IFNAR2 (previously known as IFNAR alpha and beta). IFNAR do not possess kinase activity. JAK family tyrosine kinases (TYK2, JAK1, JAK2 and JAK3) are associated with many cytokine receptors (including IFNAR) and become activated following ligand binding. Activated TYK2 and JAK1 phosphorylate signal transducer and activator of transcription 1 (STAT1) and STAT2 transcription factors: these form both homodimers (AAF/GAF: IFN alpha/gamma activated factor) and heterodimers (ISGF3: IFN stimulated gene factor 3, which complexes with IFN regulatory factor 9, IRF9), translocate into the nucleus and promote specific gene transcription. Type I IFN more strongly activate formation of ISGF3, while type II IFN (i.e. IFN gamma) mainly activates GAF/AAF. GAF/AAF and ISGF3 bind to their specific DNA sequences called IFN gamma activated (GAS) and IFN stimulated regulatory element (ISRE), respectively. IFNAR2 is alternatively spliced to generate transcripts encoding long (IFNAR2c), short (IFNAR2b) and soluble (IFNAR2a) isoforms. Conventional signaling occurs when IFN binds to IFNAR1 and IFNAR2c; IFNAR2b acts as a dominant negative modulator of IFN signaling by binding ligand but not transducing signals (decoy receptor); although IFNAR2a can bind to IFN and theoretically act as a soluble decoy receptor, evidence exists that trans-signaling (with generation of a biological response) occurs when ligand-bound soluble IFNAR2a interacts with IFNAR1. Negative regulators: SOCS (suppressor of cytokine signaling), PIAS (protein inhibitor of activated STAT) and protein phosphatases (e.g. SPH1). Besides this canonical pathway, IFN alpha can signal through "alternative" pathways including other STAT proteins, CrkL, Rap1, MAPK, Vav, RAC1, PI3K, IRS1, PMRT1, and Sin1. REFERENCES: [1] Borden EC, Nat Rev Drug Discov 2007, 6:975-90. [2] Moschos S, Cytokine Growth Factor Rev 2007, 18:451-8. [3] Takaoka A, Cell Microbiol 2006, 8:907-22. CITED MOLECULES: AAF/GAF (IFN alpha/gamma activated factor), Bcl-xL (BCL2-like 1, BCL2L1), Bcr-Abl (fusion protein Bcr-Abl), b-FGF (basic fibroblast growth factor), c-SRC (v-src sarcoma viral oncogene homolog), Cyclin D1 (CCND1), HSP90 (heat shock protein 90), IFN alpha, (interferon alpha), IFNAR (IFN alpha receptor), IFNAR1, IFNAR2a, IFNAR2b, IFNAR2c, IL-27 (interleukin 27), IRF9 (interferon regulatory factor 9, ISGF3), JAK (Janus kinase), JAK1, JSI-124 (drug), LY294002 (drug), MEK (MAP2K), MMP-2 (matrix metallopeptidase-2), NFkB (nuclear factor kappa B), PD98059 (drug), PI3K (phosphatidyl-inositol 3 kinase), PIAS (protein inhibitor of activated STAT), Resveratrol (drug), SOCS (suppressor of cytokine signaling), SOCS1, SPH1 (protein tyrosine phosphatase 1), STAT1 (signal transducer and activator of transcription 1), STAT2, STAT3, STAT5, TYK2 (tyrosine kinase 2),VEGF (vascular endothelial growth factor), WP1066 (drug).
Author: The MMMP Team (updated: February 2009)

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