Abstract
Janus kinases (Jaks) are a family of nonreceptor tyrosine kinase that include four different members, viz., Jak1, Jak2, Jak3, and Tyk2. Jaks play critical roles in immune cells functions; however, recent studies suggest they also play essential roles in nonimmune cell physiology. This review highlights the significance of epithelial Jaks in understanding the molecular basis of some of the diseases through regulation of epithelial-mesenchymal transition, cell survival, cell growth, development, and differentiation. Growth factors and cytokines produced by the cells of hematopoietic origin use Jak kinases for signal transduction in both immune and nonimmune cells. Among Jaks, Jak3 is widely expressed in both immune cells and in intestinal epithelial cells (IECs) of both humans and mice. Mutations that abrogate Jak3 functions cause an autosomal severe combined immunodeficiency disease (SCID) while activating Jak3 mutations lead to the development of hematologic and epithelial cancers. A selective Jak3 inhibitor CP-690550 (Xeljanz) approved by the FDA for certain chronic inflammatory conditions demonstrates immunosuppressive activity in rheumatoid arthritis, psoriasis, and organ transplant rejection. Here, we also focus on the consequences of Jak3-directed drugs on adverse effects in light of recent discoveries in mucosal epithelial functions of Jak3 with some information on other Jaks. Lastly, we brief on structural implications of Jak3 domains beyond the immune cells. As information about the roles of Jak3 in gastrointestinal functions and associated diseases are only just emerging, in the review, we summarize its implications in gastrointestinal wound repair, inflammatory bowel disease, obesity-associated metabolic syndrome, and epithelial cancers. Lastly, we shed lights on identifying potential novel targets in developing therapeutic interventions of diseases associated with dysfunctional IEC.
Highlights
The nonreceptor tyrosine kinases are intracellular tyrosine kinases where the family of Janus kinases (Jaks) include four members: Jak1, Jak2, Jak3, and Tyk2
Jak2 deficiency has been correlated with the human malignancies such as myeloid metaplasia with myelofibrosis characterized by excess proliferation of the cells of one or more of myeloid lineages [2]
To demonstrate the molecular basis of such symptoms, we showed that Jak3 is essential for the expression of differentiation markers in intestine and loss of jak3 gene leads to compromised differentiation through decreased expression of the differentiation markers for both enterocytes and secretory lineages
Summary
The nonreceptor tyrosine kinases are intracellular tyrosine kinases where the family of Janus kinases (Jaks) include four members: Jak, Jak, Jak, and Tyk. The GI epithelial forms a barrier between the luminal contents and the host immune system which are due to a delicate balance between different cellular processes including of cell proliferation, differentiation, and apoptosis This balance is achieved through among others the various signaling pathways that play essential roles in regulating aforementioned epithelial functions during normal development and maintaining epithelial homeostasis in gastrointestinal tract. An improved understanding of repair mediators is important for designing better therapeutic agents and promoting healing of intestinal wounds as an instigator of several chronic inflammatory diseases Apoptosis is another important epithelial function responsible for maintenance of the cellular homeostasis through balancing proliferation and cellular death in the GI tract. We illustrate Jak3’s contribution in mucosal development of gastrointestinal tissue and prevention and amelioration of chronic inflammatory conditions and shed lights on the correlation between mechanistic understanding and development of novel therapeutic interventions
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have