Eliminative Signaling by Janus Kinases: Role in the Downregulation of Associated Receptors

Abstract

Activation of cytokine receptor-associated Janus kinases (JAKs) mediates most, if not all, of the cellular responses to peptide hormones and cytokines. Consequently, JAKs play a paramount role in homeostasis and immunity. Members of this family of tyrosine kinases control the cytokine/hormone-induced alterations in cell gene expression program. This function is largely mediated through an ability to signal towards activation of the signal transducer and activator of transcription proteins (STAT) as well as towards some other pathways. Importantly, JAKs are also instrumental in tightly controlling the expression of associated cytokine and hormone receptors, and, accordingly, in regulating the cell sensitivity to these cytokines and hormones. This review highlights the enzymatic and non-enzymatic mechanisms of this regulation and discusses the importance of the ambidextrous nature of JAK as a key signaling node that integrates the combining the functions of forward signaling and eliminative signaling. Attention to the latter aspect of JAK function may contribute to emancipating our approaches to the pharmacologic modulation of JAKs.

Molecular targets of luteolin in cancer

“…However, the Janus tyrosine kinases (Jak1) and tyrosine kinase 2 (Tyk2) mediate most, if not all, cellular responses to peptide hormones, cytokines, and interferons (IFNs) and are often hyperactivated in tumors ( Muller et al , 2014 ). In fact, neither Jak1 nor Tyk2 has serine activities ( Carbone and Fuchs, 2014 ); thus, they must undergo phosphorylation before they can act. Luteolin can sensitize the antiproliferative effect of IFN by enhancing phosphorylation of Jak1 and Tyk2, thus ensuring the activation of STAT1/2, which promotes STAT1 accumulation in the nucleus and endogenous IFN-α-regulated gene expression ( Tai et al , 2014 ).…”

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“…Cellular responses to a number of cytokines and growth factors are mediated by the evolutionarily conserved JAK/ STAT signaling pathway [54]. In addition to STAT activation, the JAK family (JAK1, JAK2, TYK2, and JAK3) can activate other signaling pathways, such as MAPK and PI3K/AKT/ mTOR ( Figure 3).…”

From Science to Success? Targeting Tyrosine Kinase 2 in Spondyloarthritis and Related Chronic Inflammatory Diseases

“…for its surface expression (Ragimbeau et al, 2003;Kumar et al, 2008;Carbone and Fuchs, 2014). Specifically, kinase inactive (mutated) TYK2 stabilizes the receptor subunit it binds, such as IL-10R2, IL-12RB1, and IFNAR1, facilitating sustained surface expression and cytokine binding.…”

“…The peptide sequence of the FERM and SH2 domains dictate which specific cytokine receptors each JAK can bind ( Haan et al, 2006 ; Ferrao and Lupardus, 2017 ). JAKs bind to their respective cytokine receptors constitutively, with JAK binding often being essential for surface expression of its cognate receptor chain ( Ragimbeau et al, 2003 ; Kumar et al, 2008 ; Carbone and Fuchs, 2014 ). The pseudokinase and kinase domains are closely associated, with the former inhibiting the kinase activity in the resting state ( Lupardus et al, 2014 ).…”

“…An additional aspect of the JAK family of kinases relevant to inhibition by small molecules is that they may also undertake kinase-independent functions. TYK2 is described to have a scaffold function in cytokine signaling receptor complexes, whereby JAK binding to a cytokine receptor chain can be essential for its surface expression ( Ragimbeau et al, 2003 ; Kumar et al, 2008 ; Carbone and Fuchs, 2014 ). Specifically, kinase inactive (mutated) TYK2 stabilizes the receptor subunit it binds, such as IL-10R2, IL-12RB1, and IFNAR1, facilitating sustained surface expression and cytokine binding.…”