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Pp2a jak

Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
May 22, 2017: Oncotarget
Huading Lu, Lei Zhu, Liyi Lian, Mingwei Chen, Dehai Shi, Kun Wang
Interferon regulatory transcription factor 1 (IRF-1) regulates downstream signals of tumor necrosis factor α (TNF-α). The activity of IRF-1 is mediated by Jak/Stat signaling pathway. In this study, we found that PPAR γ coactivator-1α (PGC-1α) is able to suppress the induction of IRF-1. Treatment with TNF-α in MC3T3 cells leads to a sustainable increase in the expression of IRF-1 and its target gene cyclooxygenase 2 (COX-2). In contrast, TNF-α treatment led to a sustainable reduction in expression of PGC-1α...
April 2015: IUBMB Life
Sahana Holla, Mariola Kurowska-Stolarska, Jagadeesh Bayry, Kithiganahalli Narayanaswamy Balaji
Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents. However, several pathogens have evolved strategies to evade autophagy. Here, we demonstrated that Mycobacteria, Shigella, and Listeria but not Klebsiella, Staphylococcus, and Escherichia inhibit IFNG-induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via MTOR. Utilization of gain- or loss-of-function analyses as well as mir155-null macrophages emphasized the role of MTOR-responsive epigenetic modifications in the induction of Mir155 and Mir31...
February 2014: Autophagy
V Shanker, G Trincucci, H M Heim, H T F Duong
Mammalian cells have developed several mechanisms to sense viruses and initiate adequate responses such as production of interferons. Interferons activate the antiviral response through the Jak-STAT signalling pathway. To establish a chronic infection, viruses need to counteract this barrier of defence. The hepatitis C and hepatitis B viruses are known to up-regulate the expression of protein phosphatase 2A (PP2A). In this study, we show that PP2Ac associates with Jak1/Tyk2/STAT1 and reduces Jak1/Tyk2/STAT1 phosphorylation resulting in an impairment of the IFNα-induced HCV antiviral response...
September 2013: Journal of Viral Hepatitis
S Schenone, C Brullo, M Botta
Resistance to the Bcr-Abl inhibitors approved for the treatment of chronic myeloid leukaemia (CML) may arise from different mechanisms, including Bcr-Abl amino acid mutations, gene amplification and mechanisms independent of Bcr-Abl. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, including the synthesis of new Bcr-Abl ATPcompetitive or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors and multi-targeted kinase inhibitors...
2010: Current Medicinal Chemistry
Caroline Smal, Sabine Cardoen, Luc Bertrand, Anne Delacauw, Augustin Ferrant, Georges Van den Berghe, Eric Van Den Neste, Françoise Bontemps
Deoxycytidine kinase (dCK) is a key enzyme in the deoxynucleoside salvage pathway and in the activation of numerous nucleoside analogues used in cancer and antiviral chemotherapy. Recent studies indicate that dCK activity might be regulated through reversible phosphorylation. Here, we report the effects of a large panel of protein kinase inhibitors on dCK activity in the B-leukemia cell line EHEB, both in basal conditions and in the presence of the nucleoside analogue 2-chloro-2'-deoxyadenosine (CdA) which induces activation of dCK...
July 1, 2004: Biochemical Pharmacology
Guray Saydam, Hikmet Hakan Aydin, Fahri Sahin, Nur Selvi, Gulperi Oktem, Ender Terzioglu, Filiz Buyukkececi, Serdar Bedii Omay
Interferon-alpha (IFN-alpha)-2b is known to have antiproliferative effects on hematological malignant cells, especially chronic myelogenous leukaemia (CML). However, it can induce cytogenetical remissions in a very small percentage of the patients. Also during interferon therapy, resistance can emerge in the CML clones. K562 is an in vitro model cell line transformed from a Ph positive CML patient. It can be induced to differentiate to granulocytic and/or monocytic lineages with certain molecules. IFN-alpha-2b generally exerts its effects on CML cells by Janus family kinases (Jak/Stat) pathway, mostly through tyrosine kinase system...
August 2003: Leukemia Research
Johanna Ivaska, Lisardo Bosca, Peter J Parker
The critical dependence of receptor-triggered signals on integrin-mediated cell-substrate interactions represents a fundamental biological paradigm in health and disease. However, the molecular connections of these permissive inputs, which operate through integrin-matrix interactions, has remained largely obscure. Here we show that the serine-threonine kinase protein kinase C epsilon (PKCepsilon) functions as a signal integrator between cytokine and integrin signalling pathways. Integrins are shown to control PKCepsilon phosphorylation acutely by determining complex formation with protein phosphatase 2A (PP2A) and the upstream kinase PDK1 (phosphoinositide-dependent kinase 1)...
April 2003: Nature Cell Biology
H Liang, V J Venema, X Wang, H Ju, R C Venema, M B Marrero
Ligand binding to the angiotensin II (Ang II) AT1 receptor on vascular smooth muscle cells (VSMCs) activates the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that the JAK2 tyrosine kinase and the Src family p59 Fyn tyrosine kinase are required for Ang II-induced STAT1 tyrosine phosphorylation in VSMCs. The mitogen-activated protein kinase phosphatase, MKP-1, is required for STAT1 tyrosine dephosphorylation. In the present study, using specific enzyme inhibitors and antisense oligonucleotides, we show that Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT3 in VSMCs is mediated by p60 c-Src, whereas tyrosine dephosphorylation is mediated by calcineurin...
July 9, 1999: Journal of Biological Chemistry
D K Fuhrer, Y C Yang
Interleukin-11 is a stromal derived cytokine important in hematopoiesis. IL-11 intracellular signaling travels through cytoplasmic kinases of the Janus family. How JAKs accomplish the multiple functions of IL-11 has not been determined and until recently only a few associated downstream proteins have been identified. We present evidence here for the IL-11 induced association of PP2A, P13K, and Yes to JAK2. Reciprocal immunoprecipitations support the mutual involvement of these signaling components in IL-11 mediated signal transduction...
July 16, 1996: Biochemical and Biophysical Research Communications
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