Mucosal Epithelial Jak Kinases in Health and Diseases

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.

Null Function of Npr1 Disturbs Immune Response in Colonic Inflammation During Early Postnatal Stage

“…In a cluster of down-regulated DEGs, Jak3 is the most studied gene involved in immunological function. Jak3 deficiency exacerbates colonic inflammation with shortened colon, marked mucosal impairment, elevated neutrophil, and increased Il6 [26,27], which is consistent to the phenotype observed in our Npr1 −/− mouse model. In mice lacking Jak3, ENaC (epithelial Na + channel) activity is damaged and accompanied by sodium depletion in the colonic epithelium [28].…”

Effect of Janus Kinase 3 Inhibitor on Sebaceous Gland Regeneration during Skin Wound Healing

“…The function of Jak3 in cytoskeletal remodeling, epithelial wound healing, and mucosal homeostasis have been reported 31 . Jak3 contributes to mucosal development of gastrointestinal tissue by performing mechanistic roles in mucosal wound repair, homeostasis, epithelial barrier functions, and epithelial-mesenchymal transition 32 . In the regeneration of endothelium after vascular injury also, Jak3 can regulate the reendothelization following mechanical injury, which can modulate neointimal formation 33 .…”

Chicken-Specific Kinome Analysis of Early Host Immune Signaling Pathways in the Cecum of Newly Hatched Chickens Infected With Salmonella enterica Serovar Enteritidis

“…JAK3 is predominantly expressed in hematopoietic lineage and intestinal epithelial cells, but its role in cytokine signaling is more restricted than other JAKs with IL-2R, IL-4R, and IL-7R being the most common receptors ( Kumar et al., 2007 ; Mishra et al., 2012 ). In the intestinal epithelium, IL-2 induces activation of Jak3 to facilitate/maintain mucosal homeostasis including mucin secretion and tight junction proteins ( Kumar et al., 2021 ).…”