Interferon receptor signaling in malignancy: a network of cellular pathways defining biological outcomes

Abstract

IFNs are cytokines with important antiproliferative activity and exhibit key roles in immune surveillance against malignancies. Early work initiated over three decades ago led to the discovery of IFN receptor activated Jak-Stat pathways and provided important insights into mechanisms for transcriptional activation of IFN-stimulated genes (ISG) that mediate IFN biologic responses. Since then, additional evidence has established critical roles for other receptor-activated signaling pathways in the induction of IFN activities. These include MAPK pathways, mTOR cascades, and PKC pathways. In addition, specific miRNAs appear to play a significant role in the regulation of IFN signaling responses. This review focuses on the emerging evidence for a model in which IFNs share signaling elements and pathways with growth factors and tumorigenic signals but engage them in a distinctive manner to mediate antiproliferative and antiviral responses.

Figure 1

Type I, II, III interferon receptors subunits, associated kinases of the Janus family, and effector Stat-pathways. Note: Stat:Stat reflects multiple potential Stat:Stat compexes, as outlined in Table 2.

Figure 2

Map kinase pathways in Type I IFN signaling. GEF- Guanine exchange factor; RGT - Regulation of gene transcription; RMT - Regulation of mRNA translation; PTRGE-Post-transcriptional regulation of gene expression.

Figure 3

mTOR pathways in Type I IFN signaling. ISP-signals regulating transcription independent of Stat pathways; STP-Stat pathways.

Figure 4

Targeting and regulation of various proteins known to be involved in IFN-signaling by different miRNAs.