scholarly journals Clinical and histopathological features of myeloid neoplasms with concurrent Janus kinase 2 ( JAK2 ) V617F and KIT proto‐oncogene, receptor tyrosine kinase ( KIT ) D816V mutations

2021 ◽  
Author(s):  
Nicole Naumann ◽  
Johannes Lübke ◽  
William Shomali ◽  
Lukas Reiter ◽  
Hans‐Peter Horny ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Histopathological Features ◽  
Myeloid Neoplasms ◽  
Kit D816v

scholarly journals IGF-1R Modulation of Acute GH-Induced STAT5 Signaling: Role of Protein Tyrosine Phosphatase Activity

2013 ◽  
Vol 27 (11) ◽  
pp. 1969-1979 ◽  
Author(s):  
Yujun Gan ◽  
Yue Zhang ◽  
Ashiya Buckels ◽  
Andrew J. Paterson ◽  
Jing Jiang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phosphatase Activity ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Protein Tyrosine ◽  
Primary Osteoblasts ◽  
Ptp 1B ◽  
In Cells

GH is a potent anabolic and metabolic factor that binds its cell surface receptor (GHR), activating the GHR-associated tyrosine kinase, Janus kinase 2, which phosphorylates and activates the latent transcription factor, signal transducer and activator of transcription 5 (STAT5). Some GH actions are mediated by the elaboration of IGF-1, which exerts effects by binding and activating the heterotetrameric tyrosine kinase growth factor receptor, IGF-1R. In addition to this GH-GHR-IGF-1-IGF-1R scheme, we have demonstrated in primary osteoblasts and in islet β-cells that then deletion or silencing of IGF-1R results in diminished GH-induced STAT5 phosphorylation, suggesting that the presence of IGF-1R may facilitate GH signaling. In this study, we explore potential roles for protein tyrosine phosphatase activity in modulating GH-induced signaling, comparing conditions in which IGF-1R is present or diminished. We confirm that in mouse primary osteoblasts harboring loxP sites flanking the IGF-1R gene, infection with an adenovirus that expresses the Cre recombinase results in IGF-1R deletion and diminished acute GH-induced STAT5 phosphorylation. Furthermore, we present a new model of IGF-1R silencing, in which expression of short hairpin RNA directed at IGF-1R greatly reduces IGF-1R abundance in LNCaP human prostate cancer cells. In both models, treatment with a chemical inhibitor of protein tyrosine phosphatase-1B (PTP-1B), but not one of src homology region 2 domain-containing phosphotase-1 (SHP-1) and SHP-2, reverses the loss of GH-induced STAT5 phosphorylation in cells lacking IGF-1R but has no effect in cells with intact IGF-1R. Furthermore, expression of either a dominant-negative PTP-1B or the PTP-1B-interacting inhibitory protein, constitutive photomorphogenesis 1, also rescues acute GH-induced STAT5 signaling in IGF-1R-deficient cells but has no effect in IGF-1R replete cells. By expressing a substrate-trapping mutant PTP-1B, we demonstrate that tyrosine phosphorylated Janus kinase-2 is a PTP-1B substrate only in cells lacking IGF-1R. Collectively, our data suggest that IGF-1R positively regulates acute GH signaling by preventing access of PTP-1B activity to Janus kinase 2 and thereby preventing PTP-1B-mediated suppression of GH-induced STAT5 activation.

Erythropoiesis in the absence of janus-kinase 2: BCR-ABL induces red cell formation in JAK2−/− hematopoietic progenitors

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 2948-2957 ◽  
Author(s):  
Saghi Ghaffari ◽  
Claire Kitidis ◽  
Mark D. Fleming ◽  
Hans Neubauer ◽  
Klaus Pfeffer ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Early Stage ◽  
Fetal Liver ◽  
Erythropoietin Receptor ◽  
Janus Kinase ◽  
Tyrosine Kinase Domain ◽  
Red Cell ◽  
Janus Kinase 2 ◽  
Stage Of Development

Abstract The receptor-associated protein tyrosine kinase janus-kinase 2 (JAK2) is essential for normal red cell development and for erythropoietin receptor (EpoR) signaling. JAK2−/− embryos are severely deficient in erythropoiesis and die at an early stage of development from fetal anemia. The binding of erythropoietin (Epo) to the EpoR triggers the activation of JAK2, the phosphorylation of the EpoR, and the initiation of the EpoR signaling cascade. In addition to Epo binding to its receptor, signaling pathways downstream of the EpoR can also be stimulated by the BCR-ABL oncoprotein. This study explored whether JAK2 is required for BCR-ABL–mediated stimulation of erythropoiesis. Here, it is shown that JAK2 is constitutively tyrosine phosphorylated in cultured and primary erythroid cells expressing BCR-ABL. However, BCR-ABL effectively supports normal erythroid proliferation, differentiation, and maturation in JAK2-deficient fetal liver cells. Using mutants of BCR-ABL, this study shows that certain signaling pathways activated by BCR-ABL segments distinct from its tyrosine kinase domain are essential for rescue of erythropoiesis in JAK2−/− progenitors. The consequences of these multiple signaling pathways for normal erythroid development are discussed.

Should We Screen for Janus Kinase 2 V617F Mutation in Cerebral Venous Thrombosis?

2017 ◽  
Vol 44 (3-4) ◽  
pp. 97-104 ◽  
Author(s):  
Matthias Lamy ◽  
Paola Palazzo ◽  
Pierre Agius ◽  
Jean Claude Chomel ◽  
Jonathan Ciron ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Cerebral Venous Thrombosis ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Janus Kinase 2 ◽  
Jak2 Mutation ◽  
Venous Thromboembolic Events ◽  
V617f Mutation

Background: The presence of Janus Kinase 2 (JAK2) V617F mutation represents a major diagnostic criterion for detecting myeloproliferative neoplasms (MPN) and even in the absence of overt MPN, JAK2 V617F mutation is associated with splanchnic vein thrombosis. However, the actual prevalence and diagnostic value of the JAK2 V617F mutation in patients with cerebral venous thrombosis (CVT) are not known. The aims of this study were to assess the prevalence of JAK2 V617F mutation in a large group of consecutive CVT patients, to detect clinical, biological, and radiological features associated with the mutation, and to determine the long-term venous thrombosis recurrence rate in CVT patients with JAK2 mutation but without overt MPN in order to recommend the best preventive treatment. Methods: This was a prospective study conducted on consecutive patients with a first-ever radiologically confirmed CVT. JAK2 V617F mutation analysis was assessed in all the study subjects. JAK2 V617F-positive patients were followed up to detect new venous thrombotic events. Results: Of the 125 included subjects, 7 were found to have JAK2 V617F mutation (5.6%; 95% CI 2.3-11.2). Older age (p = 0.039) and higher platelet count (p = 0.004) were independently associated with JAK2 V617F positivity in patients without overt MPN. During a mean follow-up period of 59 (SD 46) months, 2 JAK2 V617F-positive patients presented with 4 new venous thromboembolic events. Conclusions: Screening for the JAK2 V617F mutation in CVT patients seems to be useful even in the absence of overt MPN and/or in the presence of other risk factors for CVT because of its relatively high prevalence and the risk of thrombosis recurrence.

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