TYK2: An Upstream Kinase of STATs in Cancer

Abstract

In this review we concentrate on the recent findings describing the oncogenic potential of the protein tyrosine kinase 2 (TYK2). The overview on the current understanding of TYK2 functions in cytokine responses and carcinogenesis focusses on the activation of the signal transducers and activators of transcription (STAT) 3 and 5. Insight gained from loss-of-function (LOF) gene-modified mice and human patients homozygous for Tyk2/TYK2-mutated alleles established the central role in immunological and inflammatory responses. For the description of physiological TYK2 structure/function relationships in cytokine signaling and of overarching molecular and pathologic properties in carcinogenesis, we mainly refer to the most recent reviews. Dysregulated TYK2 activation, aberrant TYK2 protein levels, and gain-of-function (GOF) TYK2 mutations are found in various cancers. We discuss the molecular consequences thereof and briefly describe the molecular means to counteract TYK2 activity under (patho-)physiological conditions by cellular effectors and by pharmacological intervention. For the role of TYK2 in tumor immune-surveillance we refer to the recent Special Issue of Cancers "JAK-STAT Signaling Pathway in Cancer".

Keywords: JAK family of protein tyrosine kinases; cytokine receptor signaling; gain-of-function mutation; signal transducer and activator of transcription; tumorigenesis; tyrosine kinase 2.

Figure 1

Cytokine receptor families signaling with the participation of TYK2 and JAK1 or JAK2. Cytokines are depicted only upon appearance in humans and mice and proof of TYK2 dependency. The color codes indicate the major STAT(s) activated by the respective cytokines. STAT1-STAT2 heterodimers combine with IFN regulatory factor (IRF) 9 and form the interferon-stimulated gene factor 3 (ISGF3) complex; * STAT activation is dependent on cell type or of less clear biological relevance.