Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Abstract

The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT-related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

Fig. 1

Canonical activation and negative regulation of JAK-STAT signaling pathways. Canonical activation of the JAK-STAT signaling pathway: cytokines bind to their corresponding receptors, which undergo a conformational change and recruit related JAKs. The JAKs undergo phosphorylation, which leads to tyrosine phosphorylation of the receptors to create docking sites for STATs. STATs are phosphorylated, dissociate from the receptor, and enter the nucleus as homodimers or heterodimers to bind specific DNA sites and regulate cytokine-related gene transcription. Negative regulation of the JAK-STAT signaling pathway: the CIS/SOCS (cytokine signaling inhibitor), PIAS (protein inhibitor of activated STAT), and PTP (protein tyrosine phosphatase) families are participants in the negative regulation of the JAK-STAT signaling pathway. The CIS/SOCS family negatively regulates the JAK-STAT pathway through direct binding of JAKs or JAK receptors to inhibit JAK kinase activity, binding of receptor tyrosine kinase sites to intercept STAT-receptor binding, or formation of enzyme complexes to degrade JAKs or STATs. The PIAS family mainly interacts with STAT dimers to inhibit STAT binding to DNA, thereby blocking JAK-STAT signal transduction. The PTP family negatively regulates the JAK/STAT pathway mainly by dephosphorylating activated receptors, JAKs, and STATs. Solid lines indicate the activation process. The dotted lines represent negative regulation

Fig. 2

The JAK-STAT signaling pathway and immune. Interactions between a large number of cytokines and the JAK-STAT pathway influence immune cell differentiation and development and exert immunoregulatory effects. IFN and IL-12 are crucial for Th1 cell differentiation and drive T-bet gene expression through STAT1 and STAT4, respectively. IL-4 upregulates GATA3 genes via STAT6 to activate Th2 cell differentiation. IL-6 and TGF play an essential role in Th17 cell differentiation via STAT3 to trigger RORt gene expression. IL-6 and IL-12 influence T follicular helper cell differentiation via STAT3 to increase Bcl-6 transcription. IL-2 induces Treg cell differentiation via the direct combination of STAT5A/B with the Foxp3 gene

Fig. 3

Mutations of the JAK-STAT pathway in human disease. Genetic mutations and polymorphisms of genes in the JAK-STAT pathway are widely involved in the pathogenesis of human diseases. The most frequent site of disease-causing mutations is within the SH2 domain in both JAKs and STATs

Fig. 4

Roles of the JAK-STAT pathway in the pathogenesis of rheumatoid arthritis and recently approved JAK inhibitors. Abnormal JAK-STAT signaling induced by multiple cytokines is regarded as the essential pathogenesis of RA. The interaction of many cytokines (including IL-1, IL-17, IL-12, IL-23, IL-6, TNF-α, and IFN-γ) and the JAK-STAT pathway mediates inflammatory responses in the synovium and causes joint destruction. There are several JAK inhibitors approved for RA treatment, including tofacitinib, baricitinib, filgotinib, upadacitinib, peficitinib, and decernotinib. The dotted lines indicate negative regulation