Disease relevance of Jak2

• Collectively, our data suggest that Jak2 is differentiation-inducing and growth-inhibitory in normal mammary epithelial cells, observations that may shed new light on the role of the Jak2-Stat5 pathway in breast cancer [1].
• Janus kinase 2: a critical target in chronic myelogenous leukemia [2].
• After in vivo administration of a high GH dose (5 microg/g body weight (BW)), the tyrosine-phosphorylation levels of JAK2 and STAT5a/b increased significantly, reaching similar values in normal and dwarf mice [3].
• BACKGROUND: A somatic activating mutation (V617F) in the JAK2 tyrosine kinase was recently discovered in the majority of patients with polycythemia vera (PV), and some with essential thrombocythemia (ET) and chronic idiopathic myelofibrosis [4].
• JAK2 V617F also induced leukocytosis and neutrophilia that was much more prominent in Balb/c mice than in B6 [4].

High impact information on Jak2

• The JAK2-GHR and JAK2-erythropoietin receptor interactions described here and in the accompanying paper provide a molecular basis for involvement of tyrosyl phosphorylation in physiological responses to these ligands and suggest a shared signaling mechanism among members of the cytokine/hematopoietin receptor family [5].
• Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase [5].
• Immunological approaches were used to establish GH-dependent complex formation between JAK2 and GHR, activation of JAK2 tyrosine kinase activity, and tyrosyl phosphorylation of both JAK2 and GHR [5].
• When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2 [6].
• Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis [7].

Chemical compound and disease context of Jak2

• Polycythemia and reticulocytosis responded to treatment with imatinib or a JAK2 inhibitor, but were unresponsive to the Src inhibitor dasatinib [4].
• Consistent with the observation that infection of CCR5-expressing cells is blocked by herbimycin A and the Jak 2 inhibitor, tyrophostin AG490, we infer that viral infectivity may be dependent on non-G-protein-coupled signal transduction pathways triggered by the infecting myxoma virus particle [8].
• A transient dephosphorylation of JAK1 and JAK2 characterises the early-phase response of murine erythroleukemia cells to the differentiation inducer hexamethylenebisacetamide [9].

Biological context of Jak2

• Growth hormone-induced Jak2 phosphorylation was enhanced by siRNA-specific knockdown of PLCgamma1 [10].
• Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction [11].
• The Wap-Cre-mediated excision of Jak2 resulted in a negative selection of differentiated alveolar cells, suggesting that Jak2 is required not only for the proliferation and differentiation of alveolar cells but also for their maintenance during lactation [12].
• A comparative analysis of Jak2-deficient mammary glands with transplants from Stat5a/b knockouts revealed that Jak2 deficiency also impairs the pregnancy-induced branching morphogenesis [12].
• Erythropoietin-dependent inhibition of apoptosis is supported by carboxyl-truncated receptor forms and blocked by dominant-negative forms of Jak2 [13].

Anatomical context of Jak2

• Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice [12].
• We generated Jak2 conditional knockout mice to study essential functions of Jak2 during mammary gland development [12].
• Moreover, Jak2 was co-immunoprecipitated with EphA4 in muscle, and both proteins were concentrated at the neuromuscular junction (NMJ) of adult muscle [14].
• Treatment of cultured C2C12 myotubes with ephrin-A1 also induced tyrosine phosphorylation of Stat3, which was abolished by the Jak2 inhibitor AG490 [14].
• Using mouse embryonic fibroblasts derived from Jak2 null embryos and their wildtype littermate controls, we demonstrated that Jak2-deficiency decouples growth hormone-receptor signaling from its downstream mediators, the signal transducer and activator of transcription (Stat) 5a and 5b [15].

Associations of Jak2 with chemical compounds

• This transformation by SFFV gp55 requires the kinase activity of sf-Stk and the presence of its extracellular domain but not expression of the EpoR or the tyrosine kinase Jak2, which is required for activation of signal transduction pathways through the EpoR [16].
• Jak2-deficient females were unable to lactate as a result of impaired alveologenesis [12].
• Similar to wild-type Bcr-Abl+ cells, inhibition of Jak2 by Ag490 treatment resulted in decrease of pSer Akt and c-Myc in imatinib-resistant cells [2].
• Coumermycin induced autophosphorylation of GyrB-Jak2 fusion proteins, thus bypassing receptor activation [17].
• There was neither enhanced tyrosine phosphorylation of cellular protein content, Cbl, or Jak2, nor serine phosphorylation of MAP kinase or Akt [18].
• Although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein [19].
• We showed that a specific JAK2 inhibitor, AG490, potently inhibited cytokine-independent cell growth induced by JAK2 L611S mutant via the induction of apoptotic cell death [20].

Physical interactions of Jak2

• PRL binding to its cognate receptor leads to receptor dimerization and activation of the tyrosine kinase Janus kinase 2 (JAK2), associated with the membrane-proximal, intracellular domain of the receptor [21].
• Consistently, antibodies directed against the extracellular domain of OB-R coprecipitated Jak2 [22].
• Electrophoretic mobility shift assays demonstrate that CD16/Jak2 activates the ability of signal transduction and activation of transcription (STAT) proteins to bind to an interferon-gamma-activated sequence oligonucleotide in a manner similar to that seen after IL-3 treatment [23].
• Mutation of Tyr(441) also blocked the ability of SOCS-1 to bind to IFNGR1 and JAK2 in response to IFNgamma and the normal down-regulation of STAT1 activation and antiviral activity [24].
• In accordance with this homology, we demonstrate that Jak-2 cofractionates and coimmunoprecipitates with caveolin-1 [25].

Enzymatic interactions of Jak2

• In turn, JAK2 phosphorylates and activates STAT5, a member of the signal transducers and activators of transcription (STAT) family [21].
• In contrast, immunoprecipitated JAK2 was not able to phosphorylate this same region of Cbl [26].
• We show here that JAK2 kinase is rapidly tyrosine phosphorylated in mouse embryonic stem cells whose pluripotentiality is maintained only by gp130-sharing cytokines after stimulation that is known to induce gp130 homodimerization [27].
• Both the receptor and Janus kinase 2 were phosphorylated after erythropoietin stimulation of J2E-NR cells [28].
• Like JAK2, HMW JAK2 is tyrosine phosphorylated in response to GH treatment of cells and is coimmunoprecipitated with anti-GHR serum [29].

Regulatory relationships of Jak2

• Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation [30].
• Stat 1 and 3 were also activated presumably downstream to JAK2 activation [31].
• Through the expression of EPOR carboxyl-terminal truncation mutants in FDC-P1 cells, we presently show that an EPOR form truncated within the ExBx2 domain efficiently activates Jak2, yet is deficient in mitogenesis [32].
• The JAK2 inhibitor AG490 blocked phosphorylation of STAT5 and PRL-induced, but not PGE1-induced, Cl- transport [33].
• Pyk2 is selectively associated with Jak2 and activated by IFN-gamma [34].

Other interactions of Jak2

• Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways [35].
• To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the ets transcription factor TEL and the cytosolic tyrosine kinase Jak2 [36].
• Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat) [12].
• Here we report a novel signaling pathway of EphA4, which involves activation of the tyrosine kinase Jak2 and the transcriptional activator Stat3 [14].
• Surprisingly, we also found that Jak2, a proto-oncogene located between Cd95 and Pten, was simultaneously inactivated in a significant fraction of the tumors analysed (24 of 34, 70.6%) [37].

Analytical, diagnostic and therapeutic context of Jak2

• METHODS AND FINDINGS: We expressed murine JAK2 WT or V617F via retroviral bone marrow transduction/transplantation in the hematopoietic system of two different inbred mouse strains, Balb/c and C57Bl/6 (B6) [4].
• Co-immunoprecipitation studies demonstrated that Jak2 became physically associated with c-Mpl relatively late in the observed time course (20-60 min), significantly later than tyrosine phosphorylation of Jak2 (1-5 min) [38].
• The erythroid-restricted growth response suggests that CID-activated Jak2 may be well suited to gene therapy applications in sickle cell anemia or beta-thalassemia [39].
• Immunocytochemistry showed that Jak2 was localized predominantly to the female pronucleus in one-cell embryos [40].
• RATIONALE: We examined the role of Jak2 kinase phosphorylation in the development of pressure overload hypertrophy in mice subjected to transverse aortic constriction (TAC) and treated with tyrphostin AG490, a pharmacological inhibitor of Jak2 [41].

References