IndraLab
Statements
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"The upstream effect of ROS on STAT3 activation not only involves the activation of Jak2 (Janus kinase 2) and TYK2 (tyrosine kinase 2) that phosphorylate STAT3 [ xref ], but also oxidation-mediated inhibition of the low molecular weight protein tyrosine phosphatase (LMW-PTP) that dephosphorylates Jak2 [ xref ]."
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"Another feasible rationale is to target downstream effectors of PBX1 such as JAK2 and STAT3 (JAK2, a tyrosine kinase that directly phosphorylates and activates STAT3) that leads to transcriptional activation of various STAT3 regulated genes that work in concert to promote tumor progression [XREF_BIBR]."
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"On the other hand, in mammals, it has been reported that hepcidin can also act as an anti-inflammatory agent inducing a signal cascade by hepcidin activated Jak2, which phosphorylates the transcription factor Stat3, subsequently provoking an anti-inflammatory transcriptional response by negative feedback."
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"To further investigate the molecular mechanism by which the JAK/STAT pathway promotes ICER expression to regulate the GABAAR α1 subunit, we inhibited the JAK/STAT pathway of rats stressed for 7 days by lateral ventricular injection of the JAK2-specific inhibitor AG490, which has been shown to significantly inhibit STAT3 phosphorylation."
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"Mechanistic studies have shown that under hypoxia-induced conditions, JAK2 phosphorylates STAT3, which is subsequently translocated to the cell core and combines with the CCNA2 promoter to regulate the expression of cyclin A2; thus, JAK2 promotes PASMC proliferation and leads to pulmonary vascular remodeling [32]."
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"Targets (2008) 12(12)
CpG MD2
LBP LPS CD14
MD2
TLR9
TLR4
MyD88 TRAF
TRIF
TRAF6
CD40L CD40
NIK/IKK
I-κB p
p65 p50
p
PPAR PPAR
RXR agonist
CNS inflammation demyelination
multiple sclerosis
Bright, Walline, Kanakasabai & Chakraborty
IL-17
IFN-γ
IL-12 IL-23
IL-12R
IL-23R
JAK2 p
TYK2 p
PPAR PPAR Agonist RXR
SOCS
STAT3 p STAT4 p p STAT5
IL-12
IL-23
Figure 2."
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"The highly soluble IL‐2R is likely produced from the enzymatic cleavage of the cell surface membrane IL‐2Rα. xref Although the functional effects of soluble IL‐2R are debated, proposed mechanisms include IL‐2 sequestration, localized inflammation regulation, and interaction with membrane IL‐2 receptors, which activates the JAK‐STAT signaling pathway. xref , xref Interleukin 23 receptor (IL‐23R) signaling modulates intestinal regulatory T cells (Tregs) by affecting cell turnover, suppression antagonism, and cholesterol efflux, potentially exacerbating chronic inflammation in patients with IBD. xref , xref Furthermore, the complex association of IL‐23R with JAK family members Jak2 and Tyk2 predominantly promotes STAT3 phosphorylation, linking the JAK‐STAT pathway to IL‐23‐mediated responses. xref Therefore, IL2RG and IL23R are crucial in immune signaling, with IL2RG overexpression potentially linked to the JAK‐STAT pathway in FCGS."
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"Curcumin ( xref ) is known to inhibit STAT3 phosphorylation by EGFR, Src, and Jak2, the upstream kinases responsible for activation of STAT3 whereas AG490 ( xref ) is a specific inhibitor of Jak2 kinase which is primarily responsible for STAT3 phosphorylation through IL-6 receptor."
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"On engagement of IL-23R, JAK2 and TYK2 become activated and phosphorylate STAT3, allowing its dimerization and translocation to the nucleus, where it can modulate transcription of target genes.28
Jak2 expression was not affected by CD200R1; however, Tyk2, which is also activated rapidly in response to IL-23R engagement, was increased in CD200R1KO ILC3s (Fig. 6F)."
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"The findings of this study show that the effect of curcumol is similar to that of the JAK2/STAT3 signal inhibitor AG490 in reducing the phosphorylation of JAK2 and STAT3 in ectopic endometrial stromal cells.In animal experiments, curcumol showed a therapeutic effect equivalent to that of AG490, and curcumol can reduce the volume of ectopic lesions and atrophy of the endometrium of EMS model rats."
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"27
Previous studies have demonstrated that JAK2 can promote the phosphorylation of STAT3 which in turn causes dimerization and nuclear translocation of STAT3 where it functions as a transcription factor to increase the expression of skeletal muscle ubiquitin E3 ligases Atrogin‐1 and MuRF1."
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"While the most straightforward conclusion of these results is that parasite triggered JAK2 activation mediates STAT3 phosphorylation, this interpretation must be treated with caution in light of recent evidence that ROP16 directly acts on STAT molecules in a manner sensitive to JAK chemical inhibition XREF_BIBR."
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"The activated JAK2 recruits and phosphorylates STAT3 for its activation and translocation to the arcuate nucleus in the hypothalamus, which regulates the expression and neuronal excitability of POMC, AgRP, and NPY, ultimately suppressing appetite, promoting energy expenditure, and reducing body weight [XREF_BIBR]."
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"We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase 2 (JAK2)–mediated phosphorylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3) by binding to JAK2, thereby decreasing the activity of downstream signaling by mTOR (mammalian target of rapamycin) and inducing cell cycle arrest."
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"These data indicated that this compound did not inhibit the phosphorylation of upstream kinases but inhibited STAT phosphorylation, most likely by inhibiting the association of STAT with JAK or cytokine receptors; however, this compound could not inhibit STAT3 phosphorylation by JAK2 and Lyn in vitro, suggesting that another cellular protein was required for this compound to inhibit STAT phosphorylation."
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"GH induced JAK2 phosphorylation was greater in knockout (KO) than in wild-type (WT) PTP-1B embryonic fibroblasts and resulted in increased tyrosine phosphorylation of STAT3 and STAT5, while overexpression of PTP-1B reduced the GH mediated activation of the acid-labile subunit gene."
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"IL6 binding to the IL6 receptor is classically followed by the activation of receptor-bound JAK1 and JAK2 kinases, which in turn phosphorylate the signal transducer and activator of transcription 3 (STAT3) that is then translocated as a dimer to the nucleus where it activates the transcription of IL6 sensitive genes xref ."
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"Through the first cascade, nicotine stimulation of alpha7 nAChR directly activates JAK2, which in turn could phosphorylate both PI3K and STAT3, as has already been demonstrated conclusively in previous studies XREF_BIBR, XREF_BIBR and is also supported by our results in MO (XREF_FIG); both activated signals would eventually, and independently, results in increased IRAK-M expression."
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"Recent studies have shown that JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3) bound to CCNA2 promoter to boost cyclin A2 production, thereby promoting PASMC proliferation and resulting in PAH. xref Meanwhile, miR‐508‐3p mimics inhibited ovarian cancer cell proliferation, migration by directly targeting the 3′‐UTR of CCNA2. xref Therefore, whether miR‐508‐3p could mediate CCNA2 to alleviate PAH required more investigation."
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"Moreover, we also certified that IL-6 could activate JAK2 and STAT3 pathways in OSCC cells.It is reported that JAK2/STAT3 can receive extracellular stimulation signals through inflammatory cytokine receptors, then induce JAK2 and STAT3 phosphorylation and regulate the expression of downstream genes [30, 31]."
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"Accumulating evidence indicates that JAK2 phosphorylates STAT3, leading to the upregulation of several factors, including B-cell lymphoma 2 (Bcl-2) [ xref ], proto-oncogene c-Myc [ xref ], cyclin D1, and vascular endothelial growth factor (VEGF) [ xref ], which are associated with cell survival and proliferation."
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"Mechanistic studies have shown that under hypoxia-induced conditions, JAK2 phosphorylates STAT3, which is subsequently translocated to the cell core and combines with the CCNA2 promoter to regulate the expression of cyclin A2; thus, JAK2 promotes PASMC proliferation and leads to pulmonary vascular remodeling [ xref ]."
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"IL-23, through binding to its receptor IL-23R, promotes the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) by janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2), allowing its entrance into the nucleus and enhancing the expression of the retinoic acid receptor-related orphan receptor gamma t (RORγt), which is responsible for the expression of IL-17 and other Th17 cytokines [ xref , xref ]."
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"The binding of ACh to this macrophage receptor results in activation of Jak2, which phosphorylates the DNA-binding transcription factor STAT3 ( xref ), decreases the nuclear translocation of the transcription factor NF-κB and reduces the transcription of the DNA-binding protein HMGB1 ( xref ), finally favoring anti-inflammatory response."
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"Binding of IL-6 family cytokines to their cognate receptors, all of which comprise a common gp130 subunit, causes the activation of Janus tyrosine kinase (JAK)-1 and JAK2 which in turn tyrosine phosphorylate signal transducer and activator of transcription (STAT)-1 and STAT3 (20, 21)."
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"141 It binds to its receptor, TPOR, on the surface of hematopoietic stem and progenitor CD34 cells (HSPCs) and results in the activation of JAK2, which leads to STAT3 phosphorylation and induction of megakaryopoiesis.142 Studies have supported overexpression of miR-494-3P in HSPCs in patients with primary myelofibrosis (PMF).143 Rontauroli et al in their study showed that an increase in expression of miR-494-3P, enhanced hematopoiesis in normal hematopoietic cells.144 Investigations have recommended that the suppressor of cytokine signaling 6 (SOCS6) is a target for miR-494-3p."
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"The metastasis of breast cancer causes the corresponding organ dysfunction and weakens the efficiency of chemotherapy to lead to higher mortality.139 Studies have shown that some small interfering RNAs (siRNAs) effectively inhibit breast cancer brain metastasis by depleting lncRNAs.140 lncRNA brain metastasis (BM)-increased JAK2 kinase activity promotes STAT3 phosphorylation to upregulate the expression of ICAM1 and CCL2, which mediated co-option of vascular and the recruitment of macrophages in the brain, respectively."
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"Accumulating evidence indicates that JAK2 phosphorylates STAT3, leading to the upregulation of several factors, including B-cell lymphoma 2 (Bcl-2) [8], proto-oncogene c-Myc [9], cyclin D1, and vascular endothelial growth factor (VEGF) [10], which are associated with cell survival and proliferation."
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"Further studies revealed that JAK2 and TYK2 were recruited to MyD88 to induce phosphorylation and activation of STAT3, promote M2-type macrophage polarization, and induced production of VEGF, bEGF and PDGF, which exhibited pro-angiogenic activity and tumorigenicity in a mouse model of pancreatic adenocarcinoma (81)."
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"The activated JAK2 recruits and phosphorylates STAT3 for its activation and translocation to the arcuate nucleus in the hypothalamus, which regulates the expression and neuronal excitability of POMC, AgRP, and NPY, ultimately suppressing appetite, promoting energy expenditure, and reducing body weight [ xref ]."
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"The finding that JAK2, STAT3 and PI3K contribute equally to nicotine-induced IRAK-M overexpression ( xref ) suggests that these three signaling molecules may be chained or converge in a common signaling pathway leading to the induction of IRAK-M. To test this hypothesis we focused our attention on those signaling routes that, according to previous studies (for more detail, see references in the corresponding section of Discussion), provide connection for the above signaling molecules: activated JAK2 can phosphorylate either STAT3 or PI3K/Akt and activated PI3K can phosphorylate STAT3."
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"JAK2 and STAT3 are key regulators in the JAK/STAT signaling pathway [ xref ], wherein JAK2 phosphorylates downstream STAT3 after recognizing extracellular signals; then, p-STAT3 regulates the expression of multiple downstream genes and participate in the regulation of apoptosis and inflammation [ xref , xref ]."
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"These data indicated that this compound did not inhibit the phosphorylation of upstream kinases but inhibited STAT phosphorylation, most likely by inhibiting the association of STAT with JAK or cytokine receptors; however, this compound could not inhibit STAT3 phosphorylation by JAK2 and Lyn in vitro , suggesting that another cellular protein was required for this compound to inhibit STAT phosphorylation."
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"These findings indicated that JAK2 inhibition by Rux in MCAO mice decreased the phosphorylation of STAT3, thus inhibiting downstream proinflammatory cytokines and acetylation of H3 and H4 on the NLRP3 promoter, resulting in a limitation of NLRP3 inflammasome activation.Rux, a selective oral JAK 1/2 inhibitor, is mainly used to treat polycythemia vera (6) and recalcitrant dermatomyositis (7), as well as myelofibrosis (8), due to its antitumor (9), immunosuppressive and anti-inflammatory functions (10)."
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"IL6 binding to the IL6 receptor is classically followed by the activation of receptor-bound JAK1 and JAK2 kinases, which in turn phosphorylate the signal transducer and activator of transcription 3 (STAT3) that is then translocated as a dimer to the nucleus where it activates the transcription of IL6 sensitive genes ."
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"Activated Jak2 phosphorylates STAT3 and SOCS3 transcription factors which bind to DNA and transactivates an anti-inflammatory gene response ( xref ), decreases the nuclear translocation of the proinflammatory cytokine transcription factor NF-κB ( xref , xref ), and reduces the transcription of the high mobility group box 1 (HMGB1) DNA-binding protein ( xref ) ( xref , adapted from Sternberg; 277)."
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"Upon inhibition of the phosphorylation of JAK2/STAT3 by the JAK2/STAT3 inhibitor AG490, the up-regulated expression and translocation of HMGB1 was reduced and EBI was ameliorated, further highlighting the contribution of JAK2/STAT3 pathway in HMGB1-mediated neuroinflammation in SAH [76]."
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"As shown in XREF_SUPPLEMENTARY, we found that the JAK2 and STAT3 double inhibitor WP1066 is able to inhibit STAT3 phosphorylation and reverse miR-204 induction upon vemurafenib treatment, while the JAK2 single inhibitor AZD1480 (XREF_SUPPLEMENTARY), the SRC inhibitor PP1 and the PI3K inhibitor wortmannin are not (XREF_SUPPLEMENTARY)."
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"Its antiapoptotic properties not only increase the resistance to chemotherapy, xref but also can enhance the activity of STAT3 transcription factor by promoting the activation of STAT3, which directly binds to STAT3, and thus contributes to the phosphorylation of STAT3 by JAK2 and its translocation to the nucleus, thereby triggering the proliferation of colon cancer cells ( xref )."
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"For example, if the phosphorylation of STAT3 by JAK2 was determined in mice, the NCBI Taxonomy ID “10090” (NCBI:txid10090) annotation should be added to the interaction.As most of disease-specific evidence comes from the literature, annotating map interactions requires maintaining a large repository of articles."
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"The binding of ACh to this macrophage receptor results in activation of Jak2, which phosphorylates the DNA-binding transcription factor STAT3 (49), decreases the nuclear translocation of the transcription factor NF-κB and reduces the transcription of the DNA-binding protein HMGB1 (50), finally favoring anti-inflammatory response."
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"Subsequently, JAK2 kinase triggered the phosphorylation of STAT3 protein, followed by separation of phosphorylated STAT3 from the IL-22 receptor, which combined with each other between the 608 Arg and the phosphorylated Tyr 705 to form a dimer in cytoplasm finally migrated to the nucleus xref ."
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"IL27 signal through their interaction with IL27 receptor [IL27R (IL27Rα/ Gp130)] on the cell surface, triggering the activation of JAK1/ JAK2, which phosphorylates and activates STAT1/STAT3 transcription factors (Pflanz et al., 2004; Huber et al., 2007; Pradhan et al., 2007; Kwock et al., 2020) ."
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"Stat3 is frequently phosphorylated and activated in the majority of breast and ovarian cancers [XREF_BIBR], where cytokines and growth factors such as IL-6 bind to specific receptors and activate JAK2 which, in turn, phosphorylates Stat3 and prompts translocation of pStat3 to the nucleus."
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"Mechanistic studies revealed that upon hypoxia‐induced activation, JAK2 phosphorylates STAT3, which then translocates into the nucleus, where it binds to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC hyperplasia along with pulmonary vascular remodelling (Figure xref )."
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"JAK2 phosphorylates and activates STAT3. xref Having shown that STAT3 was involved in enhancing IAV replication by promoting cholesterol biosynthesis, we finally tested whether JAK2 inhibition could decrease the expression of cholesterol biosynthesis-related genes and virus replication."
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"However, we provided novel evidence that OLA treatment inhibited the LPS-induced inflammatory response by significantly increasing the expression of Nrf-2/HO-1 proteins.The cytoplasmic tyrosine kinase JAK2 is able to phosphorylate and dimerize the STAT-3 leading to its activation."
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"Mechanistic studies revealed that upon hypoxia‐induced activation, JAK2 phosphorylates STAT3, which then translocates into the nucleus, where it binds to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC hyperplasia along with pulmonary vascular remodelling (Figure 7)."
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"We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2 V617F -mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2 V617F -mutant cells."
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"Mechanically, ALKBH5 activated JAK2/STAT3 signaling pathway and mediated m6A demethylation on Stat3 mRNA, but not Jak2 mRNA, which in turn promotes the phosphorylation of STAT3 to translocate into the nucleus, enhancing the transcription of hypertrophic genes, such as Nppa, ultimately leading to the development of cardiomyocyte hypertrophy."
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"Among the seven members of the STAT family, STAT3, particularly phosphorylated by JAK2, is one of the major players that has been detected in many cancers, including the brain, breast, ovarian, pancreatic, prostate, melanoma, squamous cell carcinoma [XREF_BIBR], and lung [XREF_BIBR]."
| PMC
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"Activated JAK2 auto-phosphorylates its receptors, and additionally phosphorylates STAT3, which results in the dimerization and translocation of STAT3 into the nucleus, where it binds to specific regulatory sequences to activate or repress transcription of target genes [XREF_BIBR]."
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"Moreover, the PI3K inhibitor wortmannin blocked activation of STAT3 and Akt without affecting the JAK2 activation, whereas JAK2 inhibitor AG490 suppressed the levels of phospho-STAT3, phospho-Akt, and PI3K, suggesting that PI3K activation occurs after JAK2 phosphorylation, and both PI3K and JAK2 kinases cooperate to mediate STAT3 and Akt phosphorylation."
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"JAK2 and STAT3 are key regulators in the JAK/STAT signaling pathway [39], wherein JAK2 phosphorylates downstream STAT3 after recognizing extracellular signals; then, p-STAT3 regulates the expression of multiple downstream genes and participate in the regulation of apoptosis and inflammation [39, 40]."
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"It is worth noting that while ERK2 phosphorylates the serine site of STAT3, thus inhibit the tyrosine site of STAT3 phosphorylated by JAK2 or Src kinases [43], therefore, ERK2 can inhibit the activity of STAT3 in certain signal transduction processes, which may be the reason for the downregulation of STAT3 phosphorylation.Based on these findings, we infer that luteolin's mechanism of inhibiting TNF-α-induced inflammation in HMEC-1 cells is related to Akt/MAPK/NF-κB phosphorylation or its upstream target."
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"Leptin signaling begins with the phosphorylation of janus kinase 2 (JAK2), which in turn phosphorylates signal transducer and activator of transcription 3 (STAT3), leading to its translocation to the nucleus, where it activates Pomc transcription and inhibits Npy and Agrp transcription [ xref , xref , xref , xref ]."
| PMC
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"In macrophages, IL-13 and IL-4 can activate the M2 phenotype by activating JAK2/STAT3 signaling, where IL-4 phosphorylates STAT3 and STAT6, as well as up-regulating DNA binding activity of STAT3, and IL-13 initiates Tyk2 to cascade STAT1 and STAT6, and also to increase DNA binding activity of STAT1 (119)."
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"Furthermore, JAK2 V617F, a constitutively active JAK2 mutant, phosphorylates both STAT3 and STAT5 proteins and has high frequency in patients with hematopoietic stem cell diseases, such as myeloproliferative diseases, essential thrombocythemia, polycythemia vera (PV), and idiopathic myelofibrosis (IMF) [ xref ]."
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"To ensure that the in vitro phosphorylation of stat3 by PKM2 and the R399E was at comparable physiological conditions, we compared the phosphorylation of the GST-stat3 by JAK2 and R399E. Clearly, very similar levels of stat3 phosphorylations were observed by both kinases ( xref )."
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"As mentioned above, in mammals, hepcidin can also act as an anti-inflammatory agent, inducing a signal cascade by hepcidin-activated Jak2, which phosphorylates transcription factor Stat3, subsequently provoking an anti-inflammatory transcriptional response by negative feedback [47]."
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"After knocking down the FEZF1-AS1 of KYSE150 and KYSE510 cells by the constructed lentiviral expression vector, the changes of cell cycle were detected by flow cytometry, the ability of cell proliferation by colony formation assay, the ability of cell invasion by Transwell TM invasion assay, the ability of cell migration by Transwell TM migration and scratch assay, and the protein levels of JAK2 and phosphorylated STAT3 (p-STAT3) by Western blotting."
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"Our analysis revealed that binding motifs of STAT1, STAT3 and STAT5, which are phosphorylated by JAK2, specifically associate with the observed LPS-specific hypomethylated CpGs and expression changes.JAK/STAT signaling is not directly downstream of TLR4/TLR2 receptors, and its activation requires the production of other molecules, such as IFNγ or IL-6, in order to activate the pathways autocrinally or paracrinally through their receptors (6, 47)."
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"Then the complex binds to the receptor subunit homodimer gp130 of IL-6, resulting in selective activation of JAK1, JAK2, and TYK2, which in turn promotes the recruitment and phosphorylation of STAT1, STAT3, and to a lesser extent STAT5.52–54 Ishizaki et al found various inflammatory cytokines, such as IL-6, IL-1b, and matrix metalloproteinases (MMPs), such as MMP3 and MMP9, were significantly reduced in Tyk2−/− mice.55
JAK Inhibitors Progress."
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"As JAK2-phosphorylated STAT3 is the key pathway in IL-6 effects, and RIG-I deficiency failed to promote IL-6-STAT3 activation under inhibition of JAK2 (Additional file xref : Fig. S3e), hepatic RIG-I deficiency-promoted STAT3 activation is mediated by the enhanced JAK2-STAT3 interaction."