scholarly journals The Thrombopoietin Receptor Can Mediate Proliferation without Activation of the Jak-STAT Pathway

1997 ◽  
Vol 186 (12) ◽  
pp. 1947-1955 ◽  
Author(s):  
Marion Dorsch ◽  
Pang-Dian Fan ◽  
Nika N. Danial ◽  
Paul B. Rothman ◽  
Stephen P. Goff
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transducers ◽  
Thrombopoietin Receptor ◽  
Mitogen Activated Protein ◽  
Mutant Receptors ◽  
Nonreceptor Tyrosine Kinases ◽  
Stat Pathway

Cytokine receptors of the hematopoietic receptor superfamily lack intrinsic tyrosine kinase domains for the intracellular transmission of their signals. Instead all members of this family associate with Jak family nonreceptor tyrosine kinases. Upon ligand stimulation of the receptors, Jaks are activated to phosphorylate target substrates. These include STAT (signal transducers and activators of transcription) proteins, which after phosphorylation translocate to the nucleus and modulate gene expression. The exact role of the Jak-STAT pathway in conveying growth and differentiation signals remains unclear. Here we describe a deletion mutant of the thrombopoietin receptor (c-mpl) that has completely lost the capacity to activate Jaks and STATs but retains its ability to induce proliferation. This mutant still mediates TPO-induced phosphorylation of Shc, Vav, mitogen-activated protein kinase (MAPK) and Raf-1 as well as induction of c-fos and c-myc, although at somewhat reduced levels. Furthermore, we show that both wild-type and mutant receptors activate phosphatidylinositol (PI) 3-kinase upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is inhibited in the presence of the PI 3-kinase inhibitor wortmannin. These results demonstrate that the Jak-STAT pathway is dispensable for the generation of mitogenic signals by a cytokine receptor.

scholarly journals Mitogen-Activated Protein Kinase Hog1 Mediates Adaptation to G1 Checkpoint Arrest during Arsenite and Hyperosmotic Stress

2008 ◽  
Vol 7 (8) ◽  
pp. 1309-1317 ◽  
Author(s):  
Iwona Migdal ◽  
Yulia Ilina ◽  
Markus J. Tamás ◽  
Robert Wysocki
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
Kinase Inhibitor ◽  
Hyperosmotic Stress ◽  
Mitogen Activated Protein Kinase ◽  
Hog Pathway ◽  
Cycle Arrest ◽  
Mitogen Activated Protein

ABSTRACT Cells slow down cell cycle progression in order to adapt to unfavorable stress conditions. Yeast (Saccharomyces cerevisiae) responds to osmotic stress by triggering G1 and G2 checkpoint delays that are dependent on the mitogen-activated protein kinase (MAPK) Hog1. The high-osmolarity glycerol (HOG) pathway is also activated by arsenite, and the hog1Δ mutant is highly sensitive to arsenite, partly due to increased arsenite influx into hog1Δ cells. Yeast cell cycle regulation in response to arsenite and the role of Hog1 in this process have not yet been analyzed. Here, we found that long-term exposure to arsenite led to transient G1 and G2 delays in wild-type cells, whereas cells that lack the HOG1 gene or are defective in Hog1 kinase activity displayed persistent G1 cell cycle arrest. Elevated levels of intracellular arsenite and “cross talk” between the HOG and pheromone response pathways, observed in arsenite-treated hog1Δ cells, prolonged the G1 delay but did not cause a persistent G1 arrest. In contrast, deletion of the SIC1 gene encoding a cyclin-dependent kinase inhibitor fully suppressed the observed block of G1 exit in hog1Δ cells. Moreover, the Sic1 protein was stabilized in arsenite-treated hog1Δ cells. Interestingly, Sic1-dependent persistent G1 arrest was also observed in hog1Δ cells during hyperosmotic stress. Taken together, our data point to an important role of the Hog1 kinase in adaptation to stress-induced G1 cell cycle arrest.

Tyrosine kinases regulate intracellular calcium during α2-adrenergic contraction in rat aorta

2002 ◽  
Vol 283 (4) ◽  
pp. H1673-H1680 ◽  
Author(s):  
Rebecca W. Carter ◽  
Nancy L. Kanagy
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Rat Aorta ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Intracellular Ca ◽  
Tyrphostin 23

We have demonstrated enhanced contractile sensitivity to the α2-adrenoreceptor (α2-AR) agonist UK-14304 in arteries from rats made hypertensive with chronic nitric oxide synthase (NOS) inhibition (LHR) compared with arteries from normotensive rats (NR); additionally, this contraction requires Ca2+ entry. We hypothesized that tyrosine kinases augment α2-AR contraction in LHR arteries by increasing Ca2+. The tyrosine kinase inhibitor tyrphostin 23 significantly attenuated UK-14304 contraction of denuded thoracic aortic rings from NR and LHR. However, tyrphostin 23 did not alter UK-14304 contraction in ionomycin-permeabilized aorta, which indicates that tyrosine kinases regulate intracellular Ca2+concentration. The Src family inhibitor PP1 and the epidermal growth factor receptor kinase inhibitor AG-1478 did not alter α2-AR contraction, whereas the mitogen-activated protein kinase extracellular signal-regulated kinase kinase inhibitor PD-98059 attenuated the contraction. Contraction to CaCl2 in ionomycin-permeabilized LHR rings was greater than in NR rings. UK-14304 augmented CaCl2 contraction in ionomycin-permeabilized rings from both groups but to a greater extent in LHR aorta. Together, these data suggest that α2-AR stimulates contraction via two pathways. One, which is enhanced with NOS inhibition hypertension, activates Ca2+ sensitivity and is independent of tyrosine kinases. The other is tyrosine kinase dependent and regulates intracellular Ca2+ concentration.

scholarly journals Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways.

1997 ◽  
Vol 17 (3) ◽  
pp. 1562-1571 ◽  
Author(s):  
H Luo ◽  
P Rose ◽  
D Barber ◽  
W P Hanratty ◽  
S Lee ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Critical Role ◽  
Developmental Defects ◽  
Type D ◽  
Jak Kinase ◽  
Lysine Substitution ◽  
Nonreceptor Tyrosine Kinases ◽  
Drosophila Cells ◽  
Stat Pathway

The Jak (Janus) family of nonreceptor tyrosine kinases plays a critical role in cytokine signal transduction pathways. In Drosophila melanogaster, the dominant hop(Tum-l) mutation in the Hop Jak kinase causes leukemia-like and other developmental defects. Previous studies have suggested that the Hop(Tum-l) protein might be a hyperactive kinase. Here, we report on the new dominant mutation hop(T42), which causes abnormalities that are similar to but more extreme than those caused by hop(Tum-l). We determined that Hop(T42) contains a glutamic acid-to-lysine substitution at amino acid residue 695 (E695K). This residue occurs in the JH2 (kinase-like) domain and is conserved among all Jak family members. We determined that Hop(Tum-1) and Hop(T42) both hyperphosphorylated and hyperactivated D-Stat when overexpressed in Drosophila cells. Moreover, we found that the hop(T42) phenotype was partially rescued by a reduction of wild-type D-stat activity. Finally, generation of the corresponding E695K mutation in murine Jak2 resulted in increased autophosphorylation and increased activation of Stat5 in COS cells. These results demonstrate that the mutant Hop proteins do indeed have increased tyrosine kinase activity, that the mutations hyperactivate the Hop-D-Stat pathway, and that Drosophila is a relevant system for the functional dissection of mammalian Jak-Stat pathways. Finally, we propose a model for the role of the Hop-D-Stat pathway in Drosophila hematopoiesis.

Role of tyrosine kinase and p44/42 MAPK in D2-like receptor-mediated stimulation of Na+, K+-ATPase in kidney

2002 ◽  
Vol 282 (4) ◽  
pp. F697-F702 ◽  
Author(s):  
Vihang Narkar ◽  
Tahir Hussain ◽  
Mustafa Lokhandwala
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Rat Kidney ◽  
Receptor Activation ◽  
Proximal Tubules ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Stimulation Of

Our laboratory has shown that dopamine D2-like receptor activation causes stimulation of Na+, K+-ATPase (NKA) activity in the proximal tubules of the rat kidney. The present study was designed to investigate the cellular signaling mechanisms mediating this response to D2-like receptor activation. We measured the stimulation of NKA activity by bromocriptine (D2-like receptor agonist) in the absence and presence of PD-98059 [p44/42 mitogen-activated protein kinase (MAPK) kinase inhibitor] and genistein (tyrosine kinase inhibitor) in renal proximal tubules. Both agents inhibited bromocriptine-mediated stimulation of NKA, suggesting the involvement of p44/42 MAPK and tyrosine kinase in this response. Additionally, we found that bromocriptine increased the phosphorylation of p44/42 MAPK in the proximal tubules, which was blocked by PD-98059 and genistein. These results show that D2-like receptor activation causes stimulation of NKA activity by means of a tyrosine kinase-p44/42 MAPK pathway in the proximal tubules of the kidney.

scholarly journals Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1759
Author(s):  
Liliana Montella ◽  
Margaret Ottaviano ◽  
Vittorio Riccio ◽  
Fernanda Picozzi ◽  
Gaetano Facchini ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Langerhans Cell Histiocytosis ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Mapk Signaling ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

scholarly journals Native and Polyubiquitinated Forms of Dihydroceramide Desaturase Are Differentially Linked to Human Embryonic Kidney Cell Survival

2018 ◽  
Vol 38 (23) ◽  
Author(s):  
Mariam Alsanafi ◽  
Samuel L. Kelly ◽  
Karawan Jubair ◽  
Melissa McNaughton ◽  
Rothwelle J. Tate ◽  
...  
Keyword(s):  
Cell Survival ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Sphingosine Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Dihydroceramide Desaturase ◽  
Sphingosine Kinase Inhibitor ◽  
Dependent Mechanism

ABSTRACT There is controversy concerning the role of dihydroceramide desaturase (Degs1) in regulating cell survival, with studies showing that it can both promote and protect against apoptosis. We have therefore investigated the molecular basis for these opposing roles of Degs1. Treatment of HEK293T cells with the sphingosine kinase inhibitor SKi [2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole] or fenretinide, but not the Degs1 inhibitor GT11 {N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octan-amide}, induced the polyubiquitination of Degs1 (Mr = 40 to 140 kDa) via a mechanism involving oxidative stress, p38 mitogen-activated protein kinase (MAPK), and Mdm2 (E3 ligase). The polyubiquitinated forms of Degs1 exhibit “gain of function” and activate prosurvival pathways, p38 MAPK, c-Jun N-terminal kinase (JNK), and X-box protein 1s (XBP-1s). In contrast, another sphingosine kinase inhibitor, ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], at concentrations of 25 to 50 μM failed to induce formation of the polyubiquitinated forms of Degs1. In contrast to SKi, ABC294640 (25 μM) promotes apoptosis of HEK293T cells via a Degs1-dependent mechanism that is associated with increased de novo synthesis of ceramide. These findings are the first to demonstrate that the polyubiquitination of Degs1 appears to change its function from proapoptotic to prosurvival. Thus, polyubiquitination of Degs1 might provide an explanation for the reported opposing functions of this enzyme in cell survival/apoptosis.

scholarly journals Interleukin-3–Induced Activation of the JAK/STAT Pathway Is Prolonged by Proteasome Inhibitors

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3182-3192 ◽  
Author(s):  
Bernard A. Callus ◽  
Bernard Mathey-Prevot
Keyword(s):  
Tyrosine Phosphorylation ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 3 ◽  
Short Period ◽  
Mitogen Activated Protein ◽  
Stat Pathway

Abstract One facet of cytokine receptor signaling involves the activation of signal transducers and activators of transcription (STATs). STATs are rapidly activated via tyrosine phosphorylation by Janus kinase (JAK) family members and subsequently inactivated within a short period. We investigated the effect of proteasome inhibition on interleukin-3 (IL-3) activation of the JAK/STAT pathway following stimulation of Ba/F3 cells. Treatment of Ba/F3 cells with the proteasome inhibitor,N-acetyl-l-leucinyl-l-leucinyl-norleucinal (LLnL), led to stable tyrosine phosphorylation of the IL-3 receptor, beta common (βc), and STAT5 following stimulation. The effects of LLnL were not restricted to the JAK/STAT pathway, as Shc and mitogen-activated protein kinase (MAPK) phosphorylation were also prolonged in LLnL-treated cells. Further investigation showed these stable phosphorylation events were the result of prolonged activation of JAK2 and JAK1. These observations were confirmed using pharmacologic inhibitors. In the presence of LLnL, stable phosphorylation of STAT5 and βc was abrogated if the tyrosine kinase inhibitor, staurosporine, was added. The effect of staurosporine on STAT5 phosphorylation could be overcome if the phosphatase inhibitor, vanadate, was also added, suggesting phosphorylated STAT5 could be stabilized by phosphatase, but not by proteasome inhibition per se. These observations are consistent with the hypothesis that proteasome-mediated protein degradation can modulate the activity of the JAK/STAT pathway by regulating the deactivation of JAK.

Src family kinases are involved in the meiotic maturation of porcine oocytes

2015 ◽  
Vol 27 (7) ◽  
pp. 1097 ◽  
Author(s):  
Kateřina Kheilová ◽  
Jaroslav Petr ◽  
Tereza Žalmanová ◽  
Veronika Kučerová-Chrpová ◽  
Dalibor Řehák
Keyword(s):  
Fluorescence Intensity ◽  
Tyrosine Kinases ◽  
Germinal Vesicle ◽  
Active Role ◽  
Src Family Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Meiotic Maturation ◽  
Mapk Activity ◽  
Mitogen Activated Protein

Mammalian meiotic maturation is regulated by changes in the phosphorylation state of proteins involved in signalling pathways. The regulatory proteins include the family of Src tyrosine kinases. Src family kinases (SFKs) are required for meiotic maturation of mouse oocytes, and it remains to be elucidated whether they play the same role in porcine oocytes. To clarify the role of SFKs in the meiotic maturation of porcine oocytes we used inhibition of SFKs, western blotting and immunolocalisation to determine the presence of SFKs and localisation in the oocytes and assays to determine the activity of maturation-promoting factor (MPF) and mitogen-activated protein kinase (MAPK). Inhibition of SFKs resulted in the disruption of oocyte maturation and led to a decline in MPF and MAPK activity. The fluorescence intensity of SFKs in the cytoplasm and membrane of MI oocytes decreased significantly compared with germinal vesicle oocytes. The highest fluorescence intensity for SFKs was detected on the membrane of MII oocytes. Only weak fluorescence was detected in the perichromosomal area of MI and MII oocytes. These results prove that SFKs play an active role in the meiotic maturation of porcine oocytes by regulating MPF and MAPK activity.

scholarly journals Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5147
Author(s):  
Boheng Li ◽  
Qin Wan ◽  
Zhubo Li ◽  
Wee-Joo Chng
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Janus Kinase ◽  
Signal Transducers ◽  
Lymphoid Malignancies ◽  
Stat Pathway

The Janus kinase (JAK) family are known to respond to extracellular cytokine stimuli and to phosphorylate and activate signal transducers and activators of transcription (STAT), thereby modulating gene expression profiles. Recent studies have highlighted JAK abnormality in inducing over-activation of the JAK/STAT pathway, and that the cytoplasmic JAK tyrosine kinases may also have a nuclear role. A couple of anti-JAK therapeutics have been developed, which effectively harness lymphoid cancer cells. Here we discuss mutations and fusions leading to JAK deregulations, how upstream nodes drive JAK expression, how classical JAK/STAT pathways are represented in lymphoid malignancies and the noncanonical and nuclear role of JAKs. We also summarize JAK inhibition therapeutics applied alone or synergized with other drugs in treating lymphoid malignancies.

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