What is the JAK/STAT Signaling?

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.

What is the JAK/STAT Pathway?

Receptors for cytokines, such as erythropoietin (Epo), thrombopoietin (Tpo), granulocyte-colony stimulating factor (G-CSF), type I and type II interferons (IFNs) and almost all interleukins (ILs), belong to the cytokine receptor superfamily. These receptors exhibit no intrinsic catalytic activity in their cytosolic domains and bind, through their cytosolic domains, to one or several of the four Janus kinase (JAK) cytosolic tyrosine kinase family members – namely, JAK1, JAK2, JAK3 and Tyk2. Cytokine binding to the receptor extracellular domain elicits a conformational change which rearranges preformed dimers or promotes dimer or oligomer formation from monomeric chains. This conformation is transmitted to the cytosolic juxtamembrane receptor domain, which brings into close proximity of the active and catalytic

loops of JAK proteins. These conformational changes enable JAKs to transphosphorylate and activate each other. Activated JAKs phosphorylate tyrosine residues on receptor cytosolic tails. The phosphorylated tyrosines on JAKs and receptors recruit several signaling substrates; the most prominent are members of the signal transducer and activator of transcription (STAT) family. Following JAK-mediated phosphorylation, STAT proteins dimerize and translocate to the nucleus, where they regulate gene expression.  

Figure 1 Signaling cross-talk between JAK/STAT and other pathways.

Significance of JAK/STAT Mutations in Diseases:

Figure 2 Activation and negative regulation of JAK/STAT signaling pathways.

The JAK/STAT pathway is central to signaling by cytokine receptors, a superfamily of more than 30 transmembrane proteins that recognize specific cytokines and is critical in blood formation and immune response. Many of those receptors transmit anti-apoptotic, proliferative and differentiation signals, and their expression and functions are critical for the formation of blood lineages. Several cancers, including blood malignancies, have been associated with constitutive activation of members of the STAT family, which normally require JAK-mediated tyrosine phosphorylation for transcriptional activation.

The JAK/STAT signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The JAK/STAT pathway mediates signaling by cytokines, which control survival, proliferation and differentiation of several cell types. Constitutive JAK activation leads to persistent activation of STAT transcription factors, and several cancers exhibit constitutive STAT activation, in the absence of JAK or STAT activating mutations. It's also suggested that mutated JAK proteins would be potent targets for anti-cancer therapy.

References：

[1] HU X, LI J, FU M, et al. The JAK/STAT signaling pathway: from bench to clinic [J]. Signal Transduct Target Ther, 2021, 6(1): 402.

[2] WATOWICH S S, WU H, SOCOLOVSKY M, et al. Cytokine receptor signal transduction and the control of hematopoietic cell development [J]. Annu Rev Cell Dev Biol, 1996, 12(91-128.

[3] RENAULD J C. Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators [J]. Nat Rev Immunol, 2003, 3(8): 667-76.

[4] IHLE J N, KERR I M. Jaks and Stats in signaling by the cytokine receptor superfamily [J]. Trends Genet, 1995, 11(2): 69-74.

[5] STROUD R M, WELLS J A. Mechanistic diversity of cytokine receptor signaling across cell membranes [J]. Sci STKE, 2004, 2004(231): re7.

[6] BEHRMANN I, SMYCZEK T, HEINRICH P C, et al. Janus kinase (Jak) subcellular localization revisited: the exclusive membrane localization of endogenous Janus kinase 1 by cytokine receptor interaction uncovers the Jak.receptor complex to be equivalent to a receptor tyrosine kinase [J]. J Biol Chem, 2004, 279(34): 35486-93.

[7] DARNELL J E, JR., KERR I M, STARK G R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins [J]. Science, 1994, 264(5164): 1415-21.

[8] VAINCHENKER W, CONSTANTINESCU S N. JAK/STAT signaling in hematological malignancies [J]. Oncogene, 2013, 32(21): 2601-13.

[9] BANERJEE S, BIEHL A, GADINA M, et al. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects [J]. Drugs, 2017, 77(5): 521-46.

[10] CONSTANTINESCU S N, GIRARDOT M, PECQUET C. Mining for JAK-STAT mutations in cancer [J]. Trends Biochem Sci, 2008, 33(3): 122-31.