Disease relevance of Jak2

• Furthermore, this report identifies Jak2 as a potential therapeutic target in vascular diseases in which vascular smooth muscle cell apoptosis contributes to pathological progression [1].
• Likewise, the oxidative stress, via the hypoxia/reoxygenation treatment of rat adult cardiomyocytes, produced apoptosis that was dependent upon activation of Jak2 [2].
• In conclusion, our studies demonstrate that hyperglycemia induces activation of JAK2 and the STATs in vivo via an ANG II-dependent mechanism and that these proteins may be involved in the early kidney damage associated with diabetes [3].
• Recombinant PL-Iv was shown to bind to ovarian and liver PRL receptors, stimulate the proliferation of Nb2 lymphoma cells, and activate Jak2 [4].
• After myocardial ischemia, we analysed both activated levels and total amounts of JAK1, JAK2, STAT1 and STAT3 by Western blot analyses at 0, 5, 15, 30, 60, 120 and 240 min [5].

High impact information on Jak2

• We show that EPOR-mediated activation of Jak2 leads to phosphorylation of the inhibitor of NF-kappaB (IkappaB), subsequent nuclear translocation of the transcription factor NF-kappaB, and NF-kappaB-dependent transcription of neuroprotective genes [6].
• Activation of neuronal EPO receptors (EPORs) prevents apoptosis induced by NMDA (N-methyl-d-aspartate) or NO by triggering cross-talk between the signalling pathways of Janus kinase-2 (Jak2) and nuclear factor-kappaB (NF-kappaB) [6].
• These results indicate that a PI3K-PDE3B-cAMP pathway interacting with the Janus kinase 2 (Jak2)-Stat3 pathway constitutes a critical component of leptin signaling in the hypothalamus [7].
• However, GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was 75% lower in the CRF animals [8].
• SIRPalpha-induced NO production was prevented by inhibition of the tyrosine kinase JAK2 [9].

Chemical compound and disease context of Jak2

• We tested the hypothesis that activation Jak2, which is prominently involved in the up-regulation of the renin-angiotensin system (RAS), constitutes a focal point in relaying signals triggered by a Angiotensin II (Ang II) and hypoxia/reoxygenation separately to cause an enhanced susceptibility of cardiac myocyte to apoptotic cell death [2].
• A complete cDNA clone encoding the rat JAK2 protein tyrosine kinase was isolated from an Nb2-SP (rat pre-T lymphoma cell line) cDNA library [10].
• The Galphai inhibitor pertussis toxin and the JAK2 inhibitor AG490 abrogate the inhibitory effect of RC-160 on HMW FGF-2-induced cell growth [11].
• These results suggest that herbimycin A suppresses iNOS induction by inhibition of both NF-kappa B activation caused by LPS, and tyrosine-phosphorylation of JAK2 caused by IFN-gamma in C6 glioma cells [12].

Biological context of Jak2

• We therefore examined the role that Jak2 plays in vascular smooth muscle cell apoptosis following hydrogen peroxide treatment [1].
• In vascular smooth muscle cells, Jak2 tyrosine kinase becomes activated in response to oxidative stress in the form of hydrogen peroxide [1].
• Although it has been postulated that hydrogen peroxide-induced Jak2 activation promotes cell survival, this has never been tested [1].
• Furthermore, these results suggest that the role of Jak2 in activating Stat5b may be through a mechanism other than simply inducing Stat5b phosphorylation [13].
• AG490 prevents cell death after exposure of rat astrocytes to hydrogen peroxide or proinflammatory cytokines: involvement of the Jak2/STAT pathway [14].

Anatomical context of Jak2

• In contrast, in cells expressing a Jak2 dominant negative we observed that mitochondrial membrane integrity was preserved, and no caspase-9 activation occurred [1].
• Angiotensin II activates Stat5 through Jak2 kinase in cardiac myocytes [15].
• In this study, we provide evidence that the G-protein-coupled, Ang II type I (AT1) receptor couples to activation of Stat5 through Jak2 kinase in neonatal rat ventricular myocytes [15].
• Translation of the rat Jak2 mRNA in rabbit reticulocytes results in a protein which is specifically immunoprecipitated by antibodies (Ab) recognizing JAK2, but not by Ab recognizing JAK1 [10].
• Jak2 and STAT-1 colocalized in the proximal ends of presecretory and secretory-stage ameloblasts, supporting work by others that growth hormone receptor is located at that site [16].

Associations of Jak2 with chemical compounds

• Jak2 tyrosine kinase mediates oxidative stress-induced apoptosis in vascular smooth muscle cells [1].
• However, we found evidence suggesting that AG490 reduces oxidative stress induced by H(2)O(2), which further shows that H(2)O(2) and/or derived reactive oxygen species directly activate Jak2/Stat1, but masks the actual involvement of this pathway in H(2)O(2)-induced cell death [14].
• Angiotensin II (Ang II) treatment was recently shown to activate Jak2, Stat1, and Stat3 proteins in cardiac myocytes [15].
• We recently found that activation of janus kinase 2 (JAK2) is essential for the Ang II-induced proliferation of vascular smooth muscle cells (VSMCs) and that high glucose augments Ang II-induced proliferation of VSMCs by increasing signal transduction through activation of JAK2 [17].
• Phosphorylation of STAT3 was blocked by genistein, a protein tyrosine kinase inhibitor, and AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase inhibitor [18].
• These findings reveal previously unrecognized Jak2-independent antioxidant properties of AG490, and show that Jak2-dependent Stat1 activation by peroxide is dissociated from ROS generation [19].

Physical interactions of Jak2

• Competition experiments with synthetic peptides suggest that each of the YIPP amino acids, including tyrosine 319, is important in Jak2 binding to the AT1A receptor [20].
• Co-immunoprecipitation with anti-insulin receptor antibody, anti-JAK2 antibody, and anti-IRS-1 antibody showed that JAK2 interacts with the insulin receptor and IRS-1 to form stable complexes following stimulation by insulin [21].

Enzymatic interactions of Jak2

• Immunoanalyses showed that Epo induced a significant increase in phosphorylated Janus kinase 2 and signal transducer and activator of transcription-5 expressions at 1 and 3 d and up-regulated Bcl-xL expression by 24 h after FCI but did not affect Epo receptor or NF-kappaB expression [22].

Regulatory relationships of Jak2

• Conversely, Jak1 was found expressed at a lower level compared to Jak2 and not modulated during brain maturation [23].
• Furthermore, we have shown for the first time that decidual PRL may act locally to activate the Jak2/Stat5 pathway and up-regulate important genes involved in decidual growth and placentation [24].
• These results support the main hypothesis that states that JAK2 plays a central role in the nicotinic alpha7 receptor-induced activation of the JAK2-PI-3K cascade in PC12 cells, which ultimately contribute to nAChR-mediated neuroprotection [25].
• Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes [26].
• Leptin is a JAK2-activating cytokine via the long form leptin receptor (Ob-Rb) [27].

Other interactions of Jak2

• We found no significant differences in the relative expression of either Jak2, Stat5 (a and b), or SHP-2 in the two cell populations [28].
• These results suggest that Jak2/Stat1 activation mediates cell death induced by proinflammatory cytokines and peroxides [14].
• The colocalization of Jak1, Jak2 and STAT-1 along the proximal ends of presecretory and secretory ameloblasts suggests that the interferon receptor is up-regulated in these cells as well [16].
• Furthermore, kinase-negative-Jak2, but not AG490, could inhibit Stat5b nuclear translocation and DNA binding [13].
• Jak1, Tyk2 and STAT-1, but not Jak2 or Jak3, stain was seen in the odontoblasts [16].

Analytical, diagnostic and therapeutic context of Jak2

• The desensitization of the GH-induced Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signaling pathway plays a crucial role in GH regulation of hepatic genes [29].
• Co-immunoprecipitation studies revealed that PP-2A is associated with JAK-2 in the basal state [30].
• Western blots of liver nuclear and cytoplasmic extracts to assess phosphorylated and total Stat-3 and tyrosine kinases Jak-2 and Tyk-2, immunohistochemistry to assess distribution of phosphoStat-3, and gel shift assays to assess Stat and nuclear factor kappa B binding were performed [31].
• In this study, we examined the ability of insulin to stimulate JAK2 tyrosine phosphorylation in insulin-sensitive tissues of the intact rat using immunoprecipitation and immunoblotting [21].
• In two animal models of insulin resistance the regulation of JAK2 tyrosine phosphorylation after insulin infusion paralleled the phosphorylation of the insulin receptor and of IRS-1 [21].

References