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Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregulation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are activating somatic mutations and less frequently translocations resulting in constitutively active JAK fusion proteins. JAKs have become important therapeutic targets and currently, six JAK inhibitors have been approved by the FDA for the treatment of both autoimmune diseases and hematological malignancies. However, the efficacy of the current drugs is not optimal and the full potential of JAK modulators in leukemia is yet to be harnessed. This review discusses the deregulation of JAK-STAT signaling that underlie the pathogenesis of leukemia, i.e., mutations and other mechanisms causing hyperactive cytokine signaling, as well as JAK inhibitors used in clinic and under clinical development.
Aberrant activations of the STAT3 (signal transducer and activator of transcription 3) signaling pathway are associated with cancer and inflammatory diseases. Three of the four Janus kinases, JAK1, JAK2, and Tyk2, are the major upstream kinases of STAT3 in responses to cytokine stimulations. Among them, JAK2 is the key kinase in the IL-6-induced STAT3 phosphorylation. Here we report the mechanisms of a natural compound parthenolide from the medicinal herb Feverfew in regulating the JAK/STAT3 signaling. We found that parthenolide was a potent inhibitor of JAKs. It covalently modified the Cys178, Cys243, Cys335, and Cys480 of JAK2 and suppressed its kinase activity. It also interacted with other JAKs in a similar fashion. The binding of parthenolide to JAKs was selective. It preferentially bound to the JAKs, but not to the abundant proteins, such as tubulin and actin. Parthenolide also induced reactive oxygen species (ROS), but the increased ROS did not seem to contribute to the inhibition of JAK/STAT3 signaling. Furthermore, parthenolide inhibited the IL-6-induced cancer cell migration and preferentially inhibited the growth of cancer cells that had constitutively activated STAT3. Our study suggests a novel strategy to inactivate JAKs and provides a promising anti-inflammation and anticancer drug candidate.
Treatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFNγ were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS.
Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2'-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC50 = 9.57 and 18.10 μM) and HEL (IC50 = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. Flow cytometric analysis revealed that these two compounds induced apoptosis in TF1 cells in a time and dose-dependent manner. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.
Janus kinases (JAKs) are enzymes involved in signaling pathways that affect hematopoiesis and immune cell functions. JAK1, JAK2, and JAK3 play different roles in numerous diseases of the immune system and have also been considered as potential targets for cancer therapy. In the present study, the susceptibility of the oral JAK inhibitor tofacitinib against these three JAKs was elucidated using the 500-ns molecular dynamics (MD) simulations and free energy calculations based on MM-PB(GB)SA, QM/MM-GBSA (PM3 and SCC-DFTB), and SIE methods. The obtained results revealed that tofacitinib could interact with all JAKs at the ATP-binding site via electrostatic attraction, hydrogen bond formation, and in particular van der Waals interaction. The conserved glutamate and leucine residues (E957 and L959 of JAK1, E930 and L932 of JAK2, and E903 and L905 of JAK3) located in the hinge region stabilized tofacitinib binding through strongly formed hydrogen bonds. Complexation with the incoming tofacitinib led to a closed conformation of the ATP-binding site and a decreased protein fluctuation at the glycine loop of the JAK protein. The binding affinities of tofacitinib/JAKs were ranked in the order of JAK3 > JAK2 ∼ JAK1, which are in line with the reported experimental data.
Epithelial-mesenchymal transition (EMT) is an important process associated with the metastasis of breast cancer cells. Members of the Janus kinases (JAKs) and Src family kinases (SFKs) are implicated in the regulation of an invasive phenotype in various cancer cell types. Using the pharmacological inhibitors JAK Inhibitor I (a pan-JAK inhibitor) and PP2 we investigated the role of the JAKs and SFKs, respectively, in the regulation of EMT markers in the MDA-MB-468 breast cancer cell line model of epidermal growth factor (EGF)-induced EMT. We identified selective inhibition of EGF induction of the mesenchymal marker vimentin by PP2 and JAK Inhibitor I. The effect of JAK Inhibitor I on vimentin protein induction occurred at a concentration lower than that required to significantly inhibit EGF-mediated signal transducer and activator of transcription 3 (STAT3)-phosphorylation, suggesting involvement of a STAT3-independent mechanism of EGF-induced vimentin regulation by JAKs. Despite our identification of a role for the JAK family in EGF-induced vimentin protein expression, siRNA-mediated silencing of each member of the JAK family was unable to phenocopy pharmacological inhibition, indicating potential redundancy among the JAK family members in this pathway. While SFKs and JAKs do not represent global regulators of the EMT phenotype, our findings have identified a role for members of these signaling pathways in the regulation of EGF-induced vimentin expression in the MDA-MB-468 breast cancer cell line.
Cytokines mediate a variety of effector cell functions, including cellular proliferation, differentiation, and modulation of the immune response. Many cytokines activate receptor-associated Janus kinases (JAKs) that promote tyrosine phosphorylation of signal transducers and activators of transcription (STAT) factors. Although JAK activation has been correlated with phosphorylation, the role of this tyrosine phosphorylation in the regulation of JAK1 and JAK3 remains unclear. Furthermore, the relative roles of JAK1 and JAK3 in the activation of STAT5 by interleukin-2 (IL-2) remain poorly understood.
Gain-of-function mutations in the genes encoding Janus kinases have been discovered in various haematologic diseases. Jaks are composed of a FERM domain, an SH2 domain, a pseudokinase domain and a kinase domain, and a complex interplay of the Jak domains is involved in regulation of catalytic activity and association to cytokine receptors. Most activating mutations are found in the pseudokinase domain. Here we present recently discovered mutations in the context of our structural models of the respective domains. We describe two structural hotspots in the pseudokinase domain of Jak2 that seem to be associated either to myeloproliferation or to lymphoblastic leukaemia, pointing at the involvement of distinct signalling complexes in these disease settings. The different domains of Jaks are discussed as potential drug targets. We present currently available inhibitors targeting Jaks and indicate structural differences in the kinase domains of the different Jaks that may be exploited in the development of specific inhibitors. Moreover, we discuss recent chemical genetic approaches which can be applied to Jaks to better understand the role of these kinases in their biological settings and as drug targets.
The interleukin (IL)-12-type cytokines IL-12 and IL-23 are involved in T-helper (Th) 1 and Th17 immunity, respectively. They share the IL-12 receptor β1 (IL-12Rβ1) as one component of their receptor signaling complexes, with IL-12Rβ2 as second receptor for IL-12 and IL-23R for IL-23 signal transduction. Stimulation with IL-12 and IL-23 results in activation of receptor-associated Janus kinases (Jak) and phosphorylation of STAT proteins in target cells. The Janus kinase tyrosine kinase (Tyk) 2 associates with IL-12Rβ1, whereas Jak2 binds to IL-23R and also to IL-12Rβ2. Receptor association of Jak2 is mediated by Box1 and Box2 motifs located within the intracellular domain of the receptor chains. Here we define the Box1 and Box2 motifs in IL-12Rβ1 and an unusual Jak2-binding site in IL-23R by the use of deletion and site-directed mutagenesis. Our data show that nonfunctional box motifs abolish IL-12- and IL-23-induced STAT3 phosphorylation and cytokine-dependent proliferation of Ba/F3 cells. Coimmunoprecipitation of Tyk2 by IL-12Rβ1 and Jak2 by IL‑23R supported these findings. In addition, our data demonstrate that association of Jak2 with IL-23R is mandatory for IL-12 and/or IL-23 signaling, whereas Tyk2 seems to be dispensable.
Preclinical observations that killing of chronic lymphocytic leukemia (CLL) cells was dexamethasone (DEX) were enhanced by concomitant inhibition of Bruton's tyrosine kinase and janus kinases (JAKs) motivated a phase II trial to determine if clinical responses to ibrutinib could be deepened by DEX and the JAK inhibitor ruxolitinib. Patients on ibrutinib at 420 mg daily for 2 months or with abnormal serum β2M levels after 6 months or with persistent lymphadenopathy or splenomegaly after 12 months were randomized to receive DEX 40 mg on days 1-4 of a 4-week cycle for six cycles alone (three patients) or with ruxolitinib 15 mg BID on days 1-21 of each cycle (five patients). Ruxolitinib dosing was based on a previous phase I trial. Steroid withdrawal symptoms and significantly decreased serum IgG levels occurred in all patients regardless of their exposure to ruxolitinib. A fatal invasive fungal infection was seen in a patient taking DEX without ruxolitinib. Complete responses anticipated with addition of ruxolitinib were not seen. Gene expression studies suggested ruxolitinib had turned off interferon signaling in CLL cells and turned on genes associated with the activation of NFκB by TNF-α. Ruxolitinib increased blood levels of TNF-α by cycle 3 and decreased the inhibitory cytokine IL-10. These results suggest ruxolitinib releases activating signals for CLL cells that persist in patients on ibrutinib. This inhibitory JAK signaling may contribute to the therapeutic activity of ibrutinib. Thus JAK inhibitors provide no added value with ibrutinib for disease control and should be used with caution in CLL patients. Combining glucocorticoids with ibrutinib may increase the risk of serious infects.
The ASB2α protein is the specificity subunit of an E3 ubiquitin ligase complex involved in hematopoietic differentiation and is proposed to exert its effects by regulating the turnover of specific proteins. Three ASB2α substrates have been described so far: the actin-binding protein filamins, the Mixed Lineage Leukemia protein, and the Janus kinases 2 and 3. To determine the degradation of which substrate drives ASB2α biological effects is crucial for the understanding of ASB2α functions in hematopoiesis. Here, we show that neither endogenous nor exogenously expressed ASB2α induces degradation of JAK proteins in hematopoietic cells. Furthermore, we performed molecular modeling to generate the first structural model of an E3 ubiquitin ligase complex of an ASB protein bound to one of its substrates.
Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro- and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment.
The development of resistance to chemotherapy is a major cause of cancer-related death. Elucidating the mechanisms of drug resistance should thus lead to novel therapeutic strategies. Fibroblast growth factor (FGF)-2 signaling induces the assembly of a multi-protein complex that provides tumor cells with the molecular machinery necessary for drug resistance. This complex, which involves protein kinase C (PKC) ε, v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) and p70 S6 kinase β (S6K2), enhances the selective translation of anti-apoptotic proteins such as B-cell leukaemia/lymphoma-2 (BCL-2) and inhibitors of apoptosis protein (IAP) family members and these are able to protect multiple cancer cell types from chemotherapy-induced cell death. The Janus kinases (JAKs) are most noted for their critical roles in mediating cytokine signaling and immune responses. Here, we show that JAKs have novel functions that support their consideration as new targets in therapies aimed at reducing drug resistance. As an example, we show that the Janus kinase TYK2 is phosphorylated downstream of FGF-2 signaling and required for the full phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Moreover, TYK2 is necessary for the induction of key anti-apoptotic proteins, such as BCL-2 and myeloid cell leukemia sequence (MCL) 1, and for the promotion of cell survival upon FGF-2. Silencing JAK1, JAK2 or TYK2 using RNA interference (RNAi) inhibits FGF2-mediated proliferation and results in the sensitization of tumor cells to chemotherapy-induced killing. These effects are independent of activation of signal transducer and activator of transcription (STAT) 1, STAT3 and STAT5A/B, the normal targets of JAK signaling. Instead, TYK2 associates with the other kinases previously implicated in FGF-2-mediated drug resistance. In light of these findings we hypothesize that TYK2 and other JAKs are important modulators of FGF-2-driven cell survival and that inhibitors of these kinases will likely improve the effectiveness of other cancer therapies.
St. John's Wort (Hypericum perforatum L.) flowers are commonly used in ethnomedical preparations with promising outcomes to treat inflammation both per os and by topical application. However, the underlying molecular mechanisms need to be described toward a rational, evidence-based, and reproducible use. For this purpose, the aptitude of the prominent Hypericum metabolite hypericin was assessed, along with that of its main congeners, to behave as an inhibitor of janus kinase 1, a relevant enzyme in inflammatory response. It was used a molecular modeling approach relying on docking simulations, pharmacophoric modeling, and molecular dynamics to estimate the capability of molecules to interact and persist within the enzyme pocket. Our results highlighted the capability of hypericin, and some of its analogues and metabolites, to behave as ATP-competitive inhibitor providing: (i) a likely mechanistic elucidation of anti-inflammatory activity of H. perforatum extracts containing hypericin and related compounds; and (ii) a rational-based prioritization of H. perforatum components to further characterize their actual effectiveness as anti-inflammatory agents.
Filaggrin (FLG) is a structural component of the stratum corneum that is essential for maintaining the barrier function of the skin and for the formation of natural moisturizing factors. 6,7-Dimethoxy-2,2-dimethyl-2H-chromene (Agerarin) is a bioactive compound derived from Ageratum houstonianum, a plant that is used as a traditional medicine to treat skin diseases. This study aimed to evaluate the effect of agerarin on skin inflammation in a dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model. We found that the topical administration of agerarin ameliorates atopic dermatitis-like skin lesions. We also showed that agerarin restores the reduced filaggrin (FLG) expression in DNCB-applied skin sections. Moreover, agerarin decreased phosphorylation of JAK1 and JAK2 kinases to enhance FLG expression, which was reduced by TNFα+IFNγ and IL4+IL13 treatment, in HaCaT keratinocytes. These results demonstrate the feasibility of agerarin as a possible therapeutic against conditions of skin inflammation, such as atopic dermatitis, by improving the upregulation of FLG expression.
Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the treatment of patients with high risk malignancies and hematologic conditions. These therapies are also associated with inflammatory conditions such as graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) which contribute significantly to the morbidity and mortality associated with these therapies. Recent advances in our understanding of the immunological mechanisms that underly GVHD and CRS highlight an important role for Janus kinases (JAK). JAK pathways are important for the signaling of several cytokines and are involved in the activation and proliferation of several immune cell subsets. In this review, we provide an overview of the preclinical and clinical evidence supporting the use of JAK inhibitors for acute and chronic GVHD and CRS.
Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs), resulting in the recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT)-family transcription factors. The structural arrangement of a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into the dimerization-dependent activation of JAKs and the role of oncogenic mutations in this process, the tyrosine kinase (TK) domains were separated by a distance not compatible with the trans-phosphorylation events between the TK domains. Here, we report the cryoelectron microscopy structure of a mouse JAK1 complex in a putative trans-activation state and expand these insights to other physiologically relevant JAK complexes, providing mechanistic insight into the crucial trans-activation step of JAK signaling and allosteric mechanisms of JAK inhibition.
Objectives: Anisodamine (ANI) has been used to treat a variety of diseases. However, the study of ANI in intervertebral disc degeneration (IVDD) is unclear. This study investigated the effects of ANI on degenerative nucleus pulposus cells (NPCs) and IVDD rats, and its possible mechanisms. Methods: Human nucleus pulposus cells (HNPCs) were treated with IL-1β (20 ng/ml) to simulate IVDD, and an IVDD rat model was constructed. IL-1β-induced HNPCs were treated with different concentrations (10, 20, or 40 μM) of ANI, and IVDD rats were also treated with ANI (1 mg/kg). Results: ANI treatment significantly reduced the apoptosis, caspase-3 and SA-β-gal activities, and p53 and p21 proteins expression, while promoted telomerase activity and aggrecan and collagen II synthesis in IL-1β-induced HNPCs. Moreover, the introduction of ANI inhibited the expression of IL-6, phosphorylation of JAK and STAT3, and nuclear translocation of p-STAT3 in Degenerated HNPCs. Additionally, the application of ANI abolished the effects of IL-6 on apoptosis, SA-β-gal and telomerase activity, and the expression of p53, p21, aggrecan and collagen II proteins in degenerated HNPCs. Simultaneously, ANI treatment enhanced the effects of AG490 (inhibitor of JAK/STAT3 pathway) on IL-1β-induced apoptosis, senescence and ECM degradation in HNPCs. Furthermore, ANI treatment markedly inhibited the apoptosis and senescence in the nucleus pulposus of IVDD rats, while promoted the synthesis of aggrecan and collagen II. ANI treatment obviously inhibited JAK and STAT3 phosphorylation and inhibited nuclear translocation of p-STAT3 in IVDD rats. Conclusion: ANI inhibited the senescence and ECM degradation of NPCs by regulating the IL-6/JAK/STAT3 pathway to improve the function of NPCs in IVDD, which may provide new ideas for the treatment of IVDD.
Autoimmune skin diseases are characterized by significant local and systemic inflammation that is largely mediated by the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Advanced understanding of this pathway has led to the development of targeted inhibitors of Janus kinases (JAKinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. Here we review the evolving data on the role of the JAK-STAT pathway in inflammatory dermatoses and the potential therapeutic benefit of JAK-STAT antagonism.
Janus kinases (JAKs) are found constitutively associated with cytokine receptors and are present in an inactive state prior to cytokine exposure. Activating mutations of JAKs are causative for a number of leukemias, lymphomas, and myeloproliferative diseases. In particular, the JAK2V617F mutant is found in most human cases of polycythemia vera, a disease characterized by over-production of erythrocytes. The V617F mutation is found in the pseudokinase domain of JAK2 and it leads to cytokine-independent activation of the kinase, as does the orthologous mutation in other JAK-family members. The mechanism whereby this mutation hyperactivates these kinases is not well understood, primarily due to the fact that the full-length JAK proteins are difficult to produce for structural and kinetic studies. Here we have overcome this limitation to perform a series of enzymatic analyses on full-length JAK1 and its constitutively active mutant form (JAK1V658F). Consistent with previous studies, we show that the presence of the pseudokinase domain leads to a dramatic decrease in enzymatic activity with no further decrease from the presence of the FERM or SH2 domains. However, we find that the mutant kinase, in vitro, is indistinguishable from the wild-type enzyme in every measurable parameter tested: KM (ATP), KM (substrate), kcat, receptor binding, thermal stability, activation rate, dephosphorylation rate, and inhibitor affinity. These results show that the V658F mutation does not enhance the intrinsic enzymatic activity of JAK. Rather this data is more consistent with a model in which there are cellular processes and interactions that prevent JAK from being activated in the absence of cytokine and it is these constraints that are affected by disease-causing mutations.
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