Disease relevance of JAK1

• To determine the role of the Janus tyrosine kinase (JAK)-STAT pathway in NF-kappaB activation by IFN, we examined NF-kappaB activation in JAK1-deficient mutant human fibrosarcoma cells [1].
• We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases [2].
• Pertussis toxin inhibited the C5b-9 induced JAK1 activation [3].
• Expression of vIL-6 in KSHV-related lymphoproliferative disorders has been implicated in their pathogenesis. vIL-6 has been shown to mimic a number of IL-6 activities including stimulating the growth of IL-6 dependent cell lines and activating the JAK1 and STAT1/3 pathway in HepG2 cells [4].
• Two different heterozygous mutations in the Janus kinase 1 (JAK1) gene result in complete loss of the protein in several different prostate cancer cell lines [5].
• We found three of the four leukemias with JAK1 mutations expressed mutated JAK1 at the mRNA level [6].

High impact information on JAK1

• Here we discuss one of the early signaling pathways activated by chemokines, the JAK/STAT pathway [7].
• JAK/STAT signaling effects have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote tumor cell proliferation or survival [8].
• JAK signaling globally counteracts heterochromatic gene silencing [8].
• Thus, a localized signal activates the JAK/STAT pathway in neighboring epithelial cells, causing them to become invasive [9].
• Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila [9].

Chemical compound and disease context of JAK1

• AG490 (JAK2 specific) induced apoptosis in DU145 but not in NRP-154 prostate cancer lines, whereas piceatannol (JAK1 specific) induced apoptosis in NRP-154 but not in DU145 cells [10].
• We conclude that STAT3-specific inhibitors, rather than JAK kinase-specific inhibitors, should be more useful therapeutically in treating androgen-resistant prostate cancer and that STAT3 is an appropriate target in the treatment of prostate cancer [10].
• IFN-gamma rapidly primes the macrophage via JAK1/2-STAT1 pathway so that it can subsequently undergo a slower classical type 1 activation upon exposure to T helper (Th)1 cytokines such as IFNgamma or other activators, including tumor necrosis factor and lipopolysaccharide, e.g. in intracellular killing of phagocytosed Mycobacterium tuberculosis [11].
• We found that divalent cadmium (CdCl2) inhibited ciliary neurotrophic factor (CNTF)-mediated Jak1 and Jak2 tyrosine kinase signaling in human BE(2)-C neuroblastoma cells [12].
• Silymarin protects pancreatic beta-cells against cytokine-mediated toxicity: implication of c-Jun NH2-terminal kinase and janus kinase/signal transducer and activator of transcription pathways [13].

Biological context of JAK1

• Furthermore, tyrosine phosphorylation of JAK1 was dependent on the activation of JAK2 [14].
• Moreover, IL-5-induced dimerization of IL-5R subunits caused JAK2 activation and betac phosphorylation even in the absence of JAK1 activation [14].
• Cotransfection of JAK1 or v-Src or treatment of cells with the cytokine interleukin-6 upregulated expression from ED-L1 and L1-TR reporter plasmids [15].
• This study demonstrates the ability of membrane-inserted C5b-9 to activate JAK1 and STAT3 proteins, thus defining new signalling pathway by which C5b-9 may regulate gene activation [3].
• Transfection of ERalpha-positive MCF-7 cells with an ERalpha-specific siRNA upregulated the expression of p-JAK1 [16].

Anatomical context of JAK1

• The binding of JAK1 and JAK2 to each hIL-5R subunit was also evaluated in the hIL-5-responsive cell line, TF-h5Ralpha [14].
• It was shown that in AML cells cultured in the presence of Z-VAD-fmk, TGF-beta1 pretreatment resulted in a reduction of JAK1 phosphorylation upon IL-6 stimulation [17].
• In vivo immunoassays using T cells of four different groups of individuals (S503/Q576; P503/Q576; S503/R576; P503/R576) revealed that only in case of both polymorphisms the phosphorylation of IRS-1 and IRS-2, but not JAK1 was increased [18].
• We have previously shown that IL-6 induces activation of JAK1 and JAK2 in human B cell lines [19].
• No STAT activity was detected in TCR-stimulated lymphocytes, indicating that the JAK/STAT pathway defined in this study constitutes an IL-2R-mediated signaling event which is not shared by the TCR [20].

Associations of JAK1 with chemical compounds

• Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1 [21].
• Taken together, these data indicate that serine phosphorylation of IRS-1 prevents its subsequent tyrosine phosphorylation by JAK1 and suggest that IRS-1 serine phosphorylation may play a counter-regulatory role in pathways outside the insulin signaling system [22].
• Proteasome inhibitor studies with carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone suggest an HCMV-associated enhancement of Jak1 protein degradation [23].
• Combined treatment of HCC cell lines with Ras and Jak/Stat inhibitors as well as with the demethylating agent zebularine induced a strong apoptotic response [24].
• 15-Deoxy-delta12,14-prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells [25].

Physical interactions of JAK1

• We have recently described a 116-kDa tyrosine kinase (p116) present in interleukin-2 (IL-2) receptor complexes in human YT cells that showed functional characteristics of a JAK kinase [26].
• Direct activation of the Jak/Stat system via the uPA-receptor complex may be an important mechanism for endothelial cell migration and/or proliferation during angiogenesis and after vascular injury [27].
• METHODS/RESULTS: IFN binding to its specific cell surface receptor leads to activation of the Janus family tyrosine kinase (JAK) - signal transducer and activator of transcription (STAT) pathway [28].
• Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2 [29].
• In contrast, the KIR of CIS3 showed stronger potential for both binding to JH1 and inhibition of JAK kinase activity than that of JAB [30].

Enzymatic interactions of JAK1

• Jak1 may therefore be the enzyme that phosphorylates Tyr 701 in Stat91 [31].
• The growth rates negatively correlated with levels of both IRF-1 expression and constitutively phosphorylated Jak1 [32].
• JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied [33].
• These negative regulatory effects on Ig class switching were concomitant with the ability of CD45 to dephosphorylate the induced phosphorylation of JAK1, JAK3, and signal transducer and activator of transcription 6, but not on stress-activated/mitogen-activated protein kinases [34].
• However, we were unable to show that JAK1 is tyrosine phosphorylated and activated by IL-11 under identical conditions [35].

Co-localisations of JAK1

• JAK1 and STAT3 were co-localized in alveolar type II epithelial cells where SP-B is synthesized and secreted [36].

Regulatory relationships of JAK1

• The kinetic studies indicate that tyrosine phosphorylation and activation of JAK kinases induced by IL-9 occurred within 1 minute, peaked by 5 to 10 minutes, and persisted at least for 45 minutes [37].
• Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that can be activated by Janus kinases (JAK) and that modulate gene expression in response to cytokine receptor stimulation [38].
• Further, decidual PRL through a paracrine mechanism may influence glandular epithelial function/secretions and direct gene transcription through the JAK/STAT pathway [39].
• Furthermore, while investigating the IL-6 signaling pathway leading to Mcl-1 up-regulation, we show that a janus kinase (JAK)-2 inhibitor is able to inhibit both STAT3 activation and Mcl-1 up-regulation whereas an MAP/ERK kinase (MEK) inhibitor has no effect [40].
• The JAK inhibitor AG-490 blocked cytokine-induced STAT 5 phosphorylation and proliferation of M-07e cells in a dose-dependent manner [41].

Other interactions of JAK1

• Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells [42].
• It has been suggested that the Stat proteins are substrates of the Jak protein tyrosine kinases [43].
• Moreover, the data show that JAK1 stimulation is also not sufficient for STAT3 activation [20].
• Our results suggest that methylation silencing of SOCS-3 is one of the important mechanisms of constitutive activation of the JAK/STAT pathway in cancer pathogenesis [44].
• A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses [45].

Analytical, diagnostic and therapeutic context of JAK1

• The human interleukin-5 receptor (hIL-5R) consists of a unique alpha subunit (hIL-5Ralpha) and a common beta subunit (betac) that activate two Janus kinases (JAK1 and JAK2) and a signal transducer and activator of transcription (STAT5) [14].
• Immunoprecipitation/Western blot analysis showed that HCV core could bind to JAK1/2 [46].
• The expression profiles of p-JAK1 were analyzed in 68 pairs of cancer and non-cancer breast tissues from the same infiltrating ductal carcinoma case by using immunoblotting technique [16].
• Further immunohistochemistry study showed an intense p-JAK1 staining predominantly in adjacent normal breast tissues but not the matched cancer lesions [16].
• Identification of inactivating mutations in the JAK1, SYNJ2, and CLPTM1 genes in prostate cancer cells using inhibition of nonsense-mediated decay and microarray analysis [5].

References