Therapeutic Targeting of the JAK/STAT Pathway

Abstract

Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors. The JAK/STAT PathwayCytokines are a large family of secreted proteins that play important roles in the regulation of cell growth and differentiation as well as in all aspects of the immune response. A major subgroup of cytokines exert their effects via binding to and activating a family of conserved receptors, type I and II cytokine receptors. This subfamily of cytokines consists of over 50 members in mammals and includes interferons, colonystimulating factors and many interleukins (reviewed in: [1,2]). Some hormones such as prolactin, growth hormone and erythropoietin also signal via type I cytokine receptors. The signal is transduced through a common pathway, the JAK/STAT pathway, discovered roughly 20 years ago ( fig. 1) (reviewed in [3]). JAKs or Janus kinases are a family of four tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) that selectively associate with cytokine receptor chains and mediate signalling by phosphorylating tyrosine residues on various proteins in the pathway, including themselves and the receptor chains, and STAT (signal transducer and activator of transcription) transcription factors [4]. STATs bind to the phosphorylated tyrosine residues on the receptor, and after phosphorylation by JAKs, STATs dimerize and translocate to the nucleus, where they bind to DNA and can either activate or repress transcription [5]. There are seven members of the STAT family in mammals: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. Although they can be activated by partially overlapping sets of cytokines, different STAT molecules have non-redundant biological roles [6,7]. For example, STAT1 and STAT2 mediate interferon signalling, whereas STAT4 functions in IL-12 signalling and is thus instrumental for the differentiation of T helper (Th) 1 cells. STAT6 is responsible f...

Negative Regulators of JAK/STAT Signaling in Rheumatoid Arthritis and Osteoarthritis

“…Activation of JAK/STAT by pro-inflammatory cytokines is now considered to be of major importance in driving chronic inflammation in RA [24]. This advance took on additional clinical significance which eventually resulted in the development of two JAK-selective small molecule inhibitors (SMIs), namely tofacitinib (JAK3) and ruxolitinib (JAK1/JAK2) [25,26,27,28], and especially tofacitinib, which has become part of the overall RA drug armamentarium.…”

Role of Janus-Kinases in Major Depressive Disorder

“…At present it is unknown whether Jak-3 inhibitors that were developed and presently investigated to treat rheumatoid arthritis [19] also have an antidepressant effect in humans.…”

“…Phosphorylation of Jaks is a measurement of the activity of these kinases [19]. Further, we analysed whether Stat-3, a target of Jaks [19], is phosphorylated and thereby activated after stress and whether the Jak-3 inhibitor prevents this phosphorylation (Fig. 3).…”

“…Active Jaks phosphorylate their receptors, which then bind Stat-proteins (signal transducer and activators of transcription). Their phosphorylation leads to dissociation from the receptor and migration into the nucleus to regulate protein biosynthesis [18,19]. Studies in cultured neurons revealed that pharmacological inhibition of Jak-3 inhibitor promotes neurogenesis [20].…”

STAT1 inhibitor alleviates spinal cord injury by decreasing apoptosis

“…In primary SCI, irreversible damage occurs within a short time, whereas secondary SCI involves a series of pathological alterations including focal tissue ischemia, edema, and inflammation (Cao and Dong, 2013;Hua et al, 2013). Signal transducers and activators of transcription-1 (STAT1) has been known to regulate the gene transcription of various cytokines, which further activates the Janus kinase/STAT1 pathway by phosphorylation and nuclear translocation, thus potentiating its target gene transcription (Oyinbo, 2011;Laurence et al, 2012;Aittomäki and Pesu, 2014).…”