Requirement for JAK2 inErythropoietin-Induced Signalling Pathways

Bittorf, Thomas; Jaster, Robert; Lüdtke, Britta; Kamper, Beatrice; Brock, Josef

doi:10.1016/s0898-6568(96)00121-0

Cited by 44 publications

(32 citation statements)

References 21 publications

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“…It is also possible that the MAPK and the JAK signaling pathways cooperate in FSDC to trigger the NO production induced by LPS, GM-CSF, and TNF-␣. In fact, in HCD-57 cells, a significant contribution of the cytosolic tyrosine kinase JAK2 to the erythropoietininduced activation of the Ras/MEK cascade was observed (3).…”

Section: Discussionmentioning

confidence: 99%

Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin-derived dendritic cells

Cruz

Duarte

Gonçalo³

et al. 1999

American Journal of Physiology-Cell Physiology

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. Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin-derived dendritic cells. Am. J. Physiol. 277 (Cell Physiol. 46): C1050-C1057, 1999.-In this report, we demonstrate that a fetal mouse skin-derived dendritic cell line produces nitric oxide (NO) in response to the endotoxin [lipopolysaccharide (LPS)] and to cytokines [tumor necrosis factor-␣ (TNF-␣) and granulocytemacrophage colony-stimulating factor (GM-CSF)]. Expression of the inducible isoform of NO synthase (iNOS) was confirmed by immunofluorescence with an antibody against iNOS. The tyrosine kinase inhibitor genistein decreased LPSand GM-CSF-induced nitrite (NO 2 Ϫ ) production. The effect of LPS and cytokines on NO 2 Ϫ production was inhibited by the Janus kinase 2 (JAK2) inhibitor tyrphostin B42. The p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB-203580 also reduced the NO 2 Ϫ production evoked by LPS, TNF-␣, or GM-CSF, but it was not as effective as tyrphostin B42. Inhibition of MAPK kinase with PD-098059 also slightly reduced the effect of TNF-␣ or GM-CSF on NO 2 Ϫ production. Immunocytochemistry studies revealed that the transcription factor nuclear factor-B was translocated from the cytoplasm into the nuclei of fetal skin-derived dendritic cells (FSDC) stimulated with LPS, and this translocation was inhibited by tyrphostin B42. Our results show that JAK2 plays a major role in the induction of iNOS in FSDC.mitogen-activated protein kinase; Janus kinase 2; nuclear factor-B

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Section: Discussionmentioning

confidence: 99%

Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin-derived dendritic cells

Cruz

Duarte

Gonçalo³

et al. 1999

American Journal of Physiology-Cell Physiology

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“…Several studies suggest that the EPO neuroprotective signaling pathways have some similarities to the pathways in erythropoiesis, including activations of Janus-tyrosine kinase 2 (Jak2) (Bittorf et al, 1997;Kawakami et al, 2001), signal transducers and activators of transcription (STATs) (Bittorf et al, 2000;Damen et al, 1995) and of nuclear factor kappaB (NFkB) (Figueroa et al, 2002;Matsushita et al, 2003). When the EPO molecule binds to the EPOR, a dimerization of the receptor occurs with subsequent autophosphorylation of Jak2 and receptor activation.…”

Section: Discussionmentioning

confidence: 99%

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Montero

Poulsen

Noraberg

et al. 2007

Experimental Neurology

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In addition to its well-known hematopoietic effects, erythropoietin (EPO) also has neuroprotective properties. However, hematopoietic side effects are unwanted for neuroprotection, underlining the need for EPO-like compounds with selective neuroprotective actions. One such compound, devoid of hematopoietic bioactivity, is the chemically modified, EPO-derivative carbamylerythropoietin (CEPO). For comparison of the neuroprotective effects of CEPO and EPO, we subjected organotypic hippocampal slice cultures to oxygen-glucose deprivation (OGD) or N-methyl-D-aspartate (NMDA) excitotoxicity. Hippocampal slice cultures were pretreated for 24 h with 100 IU/ml EPO (= 26 nM) or 26 nM CEPO before OGD or NMDA lesioning. Exposure to EPO and CEPO continued during OGD and for the next 24 h until histology, as well as during the 24 h exposure to NMDA. Neuronal cell death was quantified by cellular uptake of propidium iodide (PI), recorded before the start of OGD and NMDA exposure and 24 h after. In cultures exposed to OGD or NMDA, CEPO reduced PI uptake by 49 ± 3 or 35 ± 8%, respectively, compared to lesion-only controls. EPO reduced PI uptake by 33 ± 5 and 15 ± 8%, respectively, in the OGD and NMDA exposed cultures. To elucidate a possible mechanism involved in EPO and CEPO neuroprotection against OGD, the integrity of α-II-spectrin cytoskeletal protein was studied. Both EPO and CEPO significantly reduced formation of spectrin cleavage products in the OGD model. We conclude that CEPO is at least as efficient neuroprotectant as EPO when excitotoxicity is modeled in mouse hippocampal slice cultures.

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“…Antisense and sense sequences for JAK2 (30), p60 c-Src (31), p59 Fyn (32), and MKP-1 (33) have been described previously. Anti-STAT1, anti-p59 Fyn, and anti-phosphotyrosine (PY20) antibodies were obtained from Transduction Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Angiotensin II-induced Tyrosine Phosphorylation of Signal Transducers and Activators of Transcription 1 Is Regulated by Janus-activated Kinase 2 and Fyn Kinases and Mitogen-activated Protein Kinase Phosphatase 1

Venema

Eaton

et al. 1998

Journal of Biological Chemistry

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Angiotensin II (Ang II) AT 1 receptors on vascular smooth muscle cells (VSMCs) are coupled to the Janusactivated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that Ang II stimulation of VSMCs results in the tyrosine phosphorylation of JAK2 and STAT1 and the translocation of STAT1 to the nucleus. In the present study, we demonstrate using specific enzyme inhibitors and antisense oligonucleotides that both JAK2 and p59 Fyn tyrosine kinases are required for the Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT1 in VSMCs. Neither tyrosine kinase, however, appears to function upstream from the other in a phosphorylation cascade. Rather, p59 Fyn functions as an Ang II-activated docking protein for both JAK2 and STAT1, a docking interaction that may facilitate JAK2-mediated STAT1 tyrosine phosphorylation. In this study, we have also identified the nuclear dual-specificity phosphatase mitogen-activated protein kinase phosphatase 1 as the enzyme responsible for STAT1 tyrosine dephosphorylation in VSMCs.Cytokine signal transduction in hematopoietic cells includes the activation of latent transcription factors termed signal transducers and activators of transcription (STATs).1 Seven mammalian STATs are known, referred to as STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 (1). STAT proteins are activated by direct phosphorylation by cytokine receptor-associated tyrosine kinases called Janus-activated kinases (JAKs). The JAK family of tyrosine kinases includes four members known as JAK1, JAK2, JAK3, and Tyk2 (2, 3). JAKs are activated by cytokine-induced tyrosine phosphorylation. The STATs are subsequently tyrosine-phosphorylated by JAKs, accompanied by STAT homo-or heterodimerization and the translocation of STAT dimers to the nucleus, where STATs activate gene transcription through binding to specific response elements in gene promoters. Recent reports have also implicated the Src family of tyrosine kinases in the phosphorylation and activation of STAT proteins (4 -9). A role for serine phosphorylation in the activation of STATs has also been suggested (10, 11). STAT activation is transient in nature and is likely terminated by STAT tyrosine dephosphorylation because the tyrosine phosphatase inhibitor pervanadate prolongs STAT activation in cells treated with the inhibitor (12-14). However, the specific tyrosine phosphatase (or phosphatases) that participates in STAT dephosphorylation has not been identified.The JAK/STAT pathway is also utilized in signaling by the G-protein-coupled angiotensin II (Ang II) AT 1 receptor in both vascular smooth muscle cells (VSMCs) and cardiac myocytes (15-23). We have shown previously that Ang II stimulation of VSMCs induces the rapid and transient tyrosine phosphorylation of JAK2. Ang II-induced JAK2 phosphorylation is accompanied by an increased association of the enzyme with the AT 1 receptor and an increase in enzyme catalytic activity. In addition, Ang II induces the tyrosine phosphorylation of ST...

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Requirement for JAK2 inErythropoietin-Induced Signalling Pathways

Cited by 44 publications

References 21 publications

Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin-derived dendritic cells

Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin-derived dendritic cells

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Angiotensin II-induced Tyrosine Phosphorylation of Signal Transducers and Activators of Transcription 1 Is Regulated by Janus-activated Kinase 2 and Fyn Kinases and Mitogen-activated Protein Kinase Phosphatase 1

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