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”.

Targeting STAT3 and STAT5 in Cancer

“…Alternatively, targeting the specific nucleocytoplasmic STAT transport shuttles offers a creative mechanism for gaining STAT-inhibition selectivity [41]. The role and importance of targeting TYK2, in addition to the JAK1-3, in the context of inducing STAT activation, was also thoroughly discussed [42]. Similarly, the mTOR-STAT3 axis was investigated in Shwachman-Diamond syndrome as a potential kinase target in blockading persistent STAT3 activation [43].…”

TYK2 in Tumor Immunosurveillance

“…The conditional ablation of TYK2 uncovered the cell-intrinsic and -extrinsic requirements for TYK2 in the crosstalk between DCs, macrophages, and cytolytic effector cells. As the other JAK family members, TYK2 also has oncogenic properties: these are reviewed elsewhere [52,247,250].…”

“…TYK2 signaling has also been implicated in tumor-cell infiltration and metastasis in human prostate cancer patients [248], a finding recapitulated in Eµ-Myc transgenic mice, in which TYK2 deficiency reduces tumor-cell invasiveness into the liver [249]. For further details on the role of TYK2 in tumor-cell invasiveness, we refer the reader to a recent review [247].…”

“…In cancer databases, LOF or lowered TYK2 levels are generally correlated with poor prognosis, while high TYK2 levels are associated with tumorigenesis. The discrepancy may relate to the lack of information on whether TYK2 is in the tumor or the TME and/or to the lack of distinction between phosphorylated and unphosphorylated TYK2 [247].…”

Therapeutic targeting of JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors

“… 21 More recently, TYK2 mutations were described in T-ALL, particularly the V678F STAT3-activating mutation. 22 In addition, chromosomal re-arrangements resulting in fusion proteins of JAKs with other transcription factors were found in patients with haematological malignancies. A well-characterized example is translocated E26 transformation specific (ETS) leukaemia (TEL)-Jak2, which comprises the oligomerization domain of ETS family transcription factor (TEL) linked to the JH1 kinase domain of JAK2 and causes unabated activation of STAT3 and STAT5.…”