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.

Figure 1

Schematic diagram for the cellular processes involved in intestinal restitution.

Figure 2

IL-2-stimulated Jak3 activation leads to disassembly of actin filaments from the basal plane of migrating cells. (a) Planar distribution of f-actin in HT-29 Cl-19A cells at the wound edge of control cells; cells treated with IL-2; and cells treated with IL-2+WHI-P131. The lower images in each panel are the corresponding bright field images. (b) Normalized f-actin intensity for each plane as a function of the distance from the substratum [19].

Figure 3

Proposed model of IL-2-induced intestinal epithelial homeostasis [24].

Figure 4

Proposed model for the role of Jak3 in colonic mucosal health and predisposition to colitis [11].

Figure 5

Proposed models for Jak3-mediated mucosal tolerance and predisposition to obesity and MetS [1].

Figure 6

Adapter protein Shc regulates Jak3 activation through regulating Jak3 interactions with tyrosine phosphatases [40]. (a) Schematic representation of GST-Jak3-WT and mutants [39]. (b) Model for Shc-mediated Jak3 dephosphorylation [40].

Figure 7

Molecular dynamics of Jak3-mediated phosphorylation sites in β-catenin [8]. Arrows (gold, β-catenin–WT; blue, β-catenin—Y654E) indicate the corresponding positions of Ala80, Gly85, and Val166 in the modeled proteins. Note that superimposed β-catenin–WT (gold) on Y30E, Y64E, and Y86E (blue) in (b) shows overlap of the positional markers Gly85 and Val166 in the structure of the protein, indicating a close resemblance in conformation of the NTD of β-catenin–WT and β-catenin–Y30E, Y64E, and Y86E and a reversal of orientation from β-catenin–Y654E in (a).

Figure 8

Proposed models for BCRP phosphorylation mediated mucosal barrier function and predisposition to obesity [9].

Figure 9

Epithelial functions of Jak3 and some unanswered questions.