The JAK/STAT signaling pathway: from bench to clinic

Abstract

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

Fig. 1

Structure of JAKs. a Structure and conserved phosphorylation sites of the JAK family. The JAK family has four main members: JAK1, JAK2, JAK3, and TYK2. Each is composed of seven homology domains (JH), of which JH1 constitutes the kinase domain; JH2 constitutes the pseudokinase domain; a part of JH3 and JH4 together constitute the SH2 domain; and the FERM domain is composed of the JH5, JH6, and part of the JH4 domains. The conserved tyrosine phosphorylation sites in JAK1 are Y¹⁰³⁸/Y¹⁰³⁹; the conserved tyrosine phosphorylation sites in JAK2 are Y¹⁰⁰⁷/Y¹⁰⁰⁸; the conserved tyrosine phosphorylation sites in JAK3 are Y⁹⁸⁰/Y⁹⁸¹; the conserved tyrosine phosphorylation sites in Tyk2 are Y¹⁰⁵⁴/Y¹⁰⁵⁵. b Structure of JAKs and targeting sites of JAK inhibitors. Created with BioRender.com

Fig. 2

Structure and phosphorylation sites of the STAT protein family. The signal transduction and activator of transcription (STAT) family have six members: STAT1 (STAT1 has two splicing isoforms, STAT1α and STAT1β), STAT2, STAT3 (STAT3 has two splicing isoforms, STAT3α and STAT3β), STAT4, STAT5a, STAT5b, and STAT6. STATs are composed of 750–900 amino acids. From the N-terminus to the C-terminus, the domains are the nitrogen-terminal domain, coiled-coil domain, DNA-binding domain, junction domain, SH2 domain, and transcription-activation structure. "Y" represents a tyrosine phosphorylation site, and "S" represents a serine phosphorylation site. Created with BioRender.com

Fig. 3

Activation and negative regulation of JAK/STAT signaling pathways. Black arrows indicate the activation process. Red dotted arrows indicated negative regulation. Activation of the JAK/STAT signaling pathway: (1) cytokines and growth factors bind to their corresponding receptors, leading to receptor dimerization and recruitment of related JAKs; (2) JAK activation leads to tyrosine phosphorylation of the receptors and formation of docking sites for STAT; (3) STATs are phosphorylated by tyrosine; (4) STATs dissociate from the receptor to form homodimers or heterodimers; (5) STAT dimers enter the nucleus, bind to DNA, and regulate transcription. Negative regulation of the JAK/STAT signaling pathway: There are three main types of proteins involved in the negative regulation of the JAK/STAT signaling pathway: the PIAS (protein inhibitor of activated STAT), CIS/SOCS (suppressor of cytokine signaling) family, and PTPs (protein tyrosine phosphatase). PIAS mainly interacts with STAT dimers to inhibit STAT binding to DNA, thereby blocking JAK/STAT signal transduction. The CIS/SOCS family negatively regulates the JAK/STAT pathway in three ways: (1) binding to a tyrosine kinase receptor to block the recruitment of STAT; (2) binding directly to JAK to inhibit its kinase activity; (3) forming an elongin B/C-cullin5 complex that degrades JAK or STAT bound to the SOCS protein through polyubiquitination and proteasome degradation. PTPs inhibit the JAK/STAT pathway by interacting with JAK, STAT, or receptors to (1) dephosphorylate the STAT dimer; (2) interact with the receptor to dephosphorylate the related JAK; and (3) in the case of CD45 (a transmembrane PTP) inhibits the phosphorylation of JAK. Created with BioRender.com

Fig. 4

Signaling cross-talk between JAK/STAT and other pathways. (1) STAT3-p300- SMAD1 forms a complex to induce astrocyte differentiation; (2) JAK1 binds to TGFβRI and activates STAT3; (3) TGF-β also activates STAT3 via SMAD-dependent manner. (4) STAT3 inhibits SMAD3–SMAD4 complex formation and suppress SMAD3-DNA binding; (5) SMAD3 inhibits STAT3 activation via recruiting PIAS3 to STAT3; (6) TGF-β blocks IL-12 mediated JAK2 and TYK2 tyrosine phosphorylation; (7) Notch signaling suppresses JAK/STAT activation by interfering with STAT translocation to the DNA domain, and signals of JAK/STAT inhibited Notch signaling conversely. (8) Hes proteins directly bind to STAT3 and induce phosphorylation by recruiting JAK2; (9) STAT5 direct interacts with PI3K; (10) STAT5 upregulates the expression of p85α (Pik3r1), p110α (Pik3ca), and AKT1; (11) STAT3 drives the hyperacetylation of RelA via interacting with p300; (12) cyclooxygenase-2, IL-17, IL-21, and IL-23 encoded by NF-κB activate STAT3; (13) NF-κB preceded ISGF3 (a complex containing STAT1, STAT2, and IRF9 subunits) at the Nos2 promoter, thus regulating nitric oxide synthase expression; (14) IRF9-STAT1-STAT2 trimeric complex induce gene expression; (15) STAT1 regulates IRF8 synthesis; (16) STAT5 suppresses IRF8 activity; (17) STAT1 and IRF1 synergistic induce IFNγ-induced gene transcription; (18) IRF8 increases IFNγ-induced gene transcription mediated by STAT1 and IRF1. Created with BioRender.com

Fig. 5

Therapeutic targets of the JAK/STAT signaling pathway. (1) Recombinant cytokines, (2) cytokine antibodies, and (3) receptor antibodies are designed to target cytokines or receptors; (4) JAK inhibitors are designed to target JAKs; and (5) peptide inhibitors, (6) small-molecule inhibitors, (7) decoy oligonucleotides (ODNs), (8) antisense oligonucleotides (ASOs), and (9) siRNAs target STATs. Created with BioRender.com

Fig. 6

Chemical structures of JAK inhibitors.