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Figure 2 | Arthritis Research & Therapy

Figure 2

From: Genetic associations in type I interferon related pathways with autoimmunity

Figure 2

Pathways activated by type I interferons. Engagement of interferons by interferon receptors activates Jak-signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways. Jak1-Tyk2-mediated phosphorylation preferentially activates STAT1 and STAT2, which make either homodimers that induce genes with IFNγ-activated site (GAS)-dependent promoters, or heterodimers that bind IRF9 and regulate expression of the genes with interferon-stimulated response elements (ISRE). Other STAT molecules have a more restricted pattern of expression and could be activated by interferons in a cell-specific manner. p38 MAPK is activated in a series of signalling events initiated by IFNα/β and is necessary for induction of genes with both ISRE and GAS-dependent promoters. Type I interferons induce phosphorylation of a number of adaptor proteins, including members of the insulin receptor substrates (IRS1, IRS2, IRS3, and IRS4), growth-factor-receptor-bound protein 2 (GRB2)-associated binding protein 1 and 2 (GAB1 and GAB2) and members of the CRK family (CRKL, and CRK I and CRK II). Phosphorylated CRKL binds through its SH2 domain with STAT5 and activates GAS-dependent genes. Other tyrosine kinase substrates, such as Casitas B-lineage lymphoma (CBL), CBL-b, p130cas and paxillin, also bind to CRKL through the SH2 domain. The guanine-exchange factor C3G interacts with the SH3 domain of CRKL and activates small GTPase RAP 1, which participates in the regulation of cell growth, proliferation and differentiation. Activated IRS adaptors provide binding sites for the p85 regulatory subunit of PI3K, which results in the activation of the catalytic function of the p110 subunit. PI3K is known to activate a number of downstream signalling molecules affecting all aspects of cell biology. Thus, tissue-specific isoforms of protein kinase C (PKC) family, PKCδ, PKCε, PKCθ and PKCη, phosphorylate serine residues in the STAT factors and p38 MAPK. Pharmacological inhibitors that block the activity of distinct PKCs affect the expression of the interferon-responsive genes. The PI3K-AKT signalling cascade mediates survival signals in a cell-type-restricted manner, inducing both anti-apoptopic and pro-apoptotic pathways, and translation of cap-dependent transcripts. Type I interferons activate two members of Src family of kinases, Fyn in T cells and Lyn in B cells. Lyn kinase in its turn phosphorylates B-cell-specific adaptor protein BANK1, facilitating formation of a complex between BANK1, BLK kinase and IP3 receptor 2 (IP3R2). Yellow stars, genes with strong evidence for association with autoimmune diseases; black stars, genes with inconsistent association. ISG, interferon stimulated genes; OAS, 2',5'-oligoadenylate synthase; PKR, protein kinase dsRNA-dependent serine-threonine kinase.

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