Disease relevance of Jak1

• However, Jak1-deficient, v-abl-transformed cell lines were more tumorgenic than wild-type cells when transplanted subcutaneously into severe combined immunodeficient (SCID) mice or injected intravenously into nude mice [1].
• STAT3 activation was inhibited by either pharmacologically (AG490) through its upstream janus kinase (JAK2) or by a dominant-negative STAT3 adenovirus [2].
• At the other end of the spectrum, JAK fusion proteins have been shown to play a role in leukemias [3].
• The nonreceptor tyrosine kinases Jak1 and Jak3, which bind to the v-Abl oncoprotein, are constitutively activated in cells transformed with the Abelson murine leukemia virus [4].
• We studied macrophage deactivation by examining the expression of a panel of IFN-gamma-inducible genes and activation of Janus Kinase (JAK)-STAT pathway in Mycobacterium avium-infected macrophages [5].

High impact information on Jak1

• Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway [6].
• Cytokines exert their biological effect through binding to cell-surface receptors that are associated with one or more members of the JAK family of cytoplasmic tyrosine kinases [7].
• Overexpression of either Jak1 or Jak2 stimulated p91 DNA-binding activity and p91-dependent transcription [8].
• Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor [9].
• Coimmunoprecipitation experiments revealed that in these cells v-Abl was physically associated with Jak1 and Jak3 [10].

Chemical compound and disease context of Jak1

• Activation of the JAK1-STAT5 pathway by binding of the Friend virus gp55 glycoprotein to the erythropoietin receptor [11].
• A transient dephosphorylation of JAK1 and JAK2 characterises the early-phase response of murine erythroleukemia cells to the differentiation inducer hexamethylenebisacetamide [12].
• We investigated the functionality of the Jak1 SH2 domain by stably reconstituting Jak1-defective human fibrosarcoma cells U4C with endogenous amounts of Jak1 in which the crucial arginine residue Arg466 within the SH2 domain has been replaced by lysine [13].
• 1,25 dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis [14].
• Treatment of Arf(-/-), p210(Bcr-Abl)-positive pre-B cells with imatinib together with an inhibitor of JAK kinases abrogates this resistance, suggesting that this combination may prove beneficial in the treatment of BCR-ABL-positive acute lymphoblastic leukemia [15].

Biological context of Jak1

• Stat6 tyrosine phosphorylation and Jak1 activation were ablated in the liver of ConA-injected PKCzeta-/- mice and in IL-4-stimulated PKCzeta-/- fibroblasts [16].
• Jak1 deficiency was associated with a loss in the ability of interferon-gamma (IFN-gamma)to induce growth arrest and/or apoptosis of v-abl-transformed pre-B cells or tumor growth in SCID mice [1].
• Unexpectedly, we found the intracellular domain of interleukin-4 receptor alpha chain to evoke cell proliferation and activation of tyrosine kinase Jak1 as well as of transcription factor Stat6 upon homodimerization [17].
• Using reporter gene assays, we further showed that activation of Stat3 and possibly of Jak1 by v-Src were mediated through a Ras-independent pathway [18].
• The Role of Interleukin-11 in Pregnancy Involves Up-Regulation of {alpha}2-Macroglobulin Gene through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 Pathway in the Decidua [19].

Anatomical context of Jak1

• Jak1 deficiency leads to enhanced Abelson-induced B-cell tumor formation [1].
• In the present studies, we have identified a series of end stage B cell (plasma cell) lines that fail to express Jak1, but phosphorylate STAT3 in response to IL-6 [20].
• The overlapping and distinct protein tyrosine phosphorylation and activation of the same JAK1 kinase in T lymphocytes strongly suggests that IL-4 and IL-9 share the common signal transduction pathways and that the specificity for each cytokine could be achieved through the unique tyrosine-phosphorylated proteins triggered by individual cytokines [21].
• Mouse brain microglia express interleukin-15 and its multimeric receptor complex functionally coupled to Janus kinase activity [22].
• Possible involvement of Janus kinase Jak2 in interferon-gamma induction of nitric oxide synthase in rat glial cells [23].

Associations of Jak1 with chemical compounds

• Both cytokines induced activation of Stat5, but only IL-7 induced activation of the Janus family kinases Jak1 and Jak3 [24].
• However, using glutathione S-transferase fusion proteins containing amino- and carboxyl-terminal deletions of the betaL cytoplasmic domain, we demonstrate that the main Jak1-binding region (corresponding to AAs 300-346 on the beta subunit) is distinct from the Box 1 domain (AAs 287-295) [25].
• In contrast, JAK-1 was not coprecipitated when coexpressed with a receptor alpha chain mutant containing alanine substitutions for the functionally critical residues 266-269 (LPKS) [26].
• Janus kinase-signal transducer and activator of transcription mediates phosphatidic acid-induced interleukin (IL)-1beta and IL-6 production [27].
• Activation of the JAK/STAT pathway, which is involved in cytokine signaling, was investigated in the gp55 signaling mediated by the erythropoietin receptor [28].

Physical interactions of Jak1

• These results demonstrate that JAK protein tyrosine kinases couple PRL binding to tyrosine phosphorylation and proliferation [29].
• Although JAK2 was capable of associating with all three of the chimeras, JAK1 co-precipitated only with the gp130 chimera [30].

Regulatory relationships of Jak1

• In the case of growth factors whose receptors have intrinsic tyrosine protein kinase activity, it is thought that Stat proteins can be activated either directly by the receptor or indirectly through JAK proteins [31].
• As the LIF-induced Jak1/STAT3 pathway has been reported to play a crucial role in self-renewal of mESCs, we sought to determine if Jak2, which is also expressed in mESCs, might also be involved in the pathway [32].
• However, only in BAF-3 cells expressing the PRL-R does PRL induce rapid and transient tyrosine phosphorylation of JAK1 [29].
• IL-3 induces phosphorylation of the above proteins with the exception of mpl and also causes weak JAK1 phosphorylation [33].
• Erythropoietin and interleukin-2 activate distinct JAK kinase family members [34].

Other interactions of Jak1

• IL-4 initiates transmembrane signaling through two types of receptor complexes comprising the IL-4Ralpha subunit and the associated Janus kinase 1 (Jak1) as common essential components [35].
• Constitutive activation of JAK1 in Src-transformed cells [36].
• Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases [37].
• Inhibition of JAK activity resulted in partial suppression of transient phosphorylation of STAT5 and no suppression of sustained phosphorylation of STAT5 [38].
• Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factor- and Jak/Stat-signaling pathways in 3T3-L1 adipocytes [39].

Analytical, diagnostic and therapeutic context of Jak1

• This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism [40].
• To determine if additional members of JAK kinase family exist, we designed a polymerase chain reaction based strategy which resulted in the identification of a new member of the JAK kinase family [41].
• Janus kinase (JAK) 3-deficient mice were not able to reject allogeneic islet allografts [42].
• Pretreatment with the JAK inhibitor AG-490 20 min before the six occlusion/reperfusion cycles blocked the enhanced tyrosine phosphorylation of JAK1 and JAK2 and the increased tyrosine phosphorylation, nuclear translocation, and enhanced DNA-binding activity of STAT1 and STAT3 [43].
• Molecular cloning of the murine JAK1 protein tyrosine kinase and its expression in the mouse central nervous system [44].

References