A Thrombopoietin Receptor Mutant Deficient in Jak-STAT Activation Mediates Proliferation But Not Differentiation in UT-7 Cells

Blood ◽  
1999 ◽  
Vol 94 (8) ◽  
pp. 2676-2685 ◽  
Author(s):  
Marion Dorsch ◽  
Nika N. Danial ◽  
Paul B. Rothman ◽  
Stephen P. Goff

Thrombopoietin (TPO) stimulates proliferation and differentiation of cells of the megakaryocytic lineage. It exerts its function by binding and activating c-mpl, a member of the hematopoietic receptor superfamily. Upon binding of TPO to its receptor, numerous signaling events are triggered. These include activation of the Jak-STAT (signal transducers and activators of transcription) pathway, mitogen-activated protein kinase (MAPK), Tec, and phospatidylinositol (PI) 3-kinase and phosphorylation of Shc and Vav. The contribution of different signaling pathways to the induction of specific cellular processes such as proliferation and differentiation is incompletely understood. We have previously described a mutant of c-mpl that fails to activate the Jak-STAT pathway but nevertheless retains its ability to mediate proliferation and activation of most signaling events in the murine hematopoietic precursor cell lines BAF/3 and 32D. We confirm here the ability of this mutant to mediate proliferation in the absence of Jak-STAT activation in the human cell line UT-7 and further show that this mutant fails to mediate TPO-induced megakaryocytic differentiation. Comparison of the signaling capacity of this mutant in UT-7 and BAF/3 cells shows considerable cell-type–specific differences. Whereas in BAF/3 cells the mutant still mediates activation of Shc, MAPK, Vav, and PI 3-kinase at levels comparable to the wild-type receptor, these events are strongly diminished in UT-7 cells expressing the mutant. Furthermore, we show that the C-terminal 25 amino acid residues of the receptor mutant are crucial for the mitogenic response in UT-7 cells.

2017 ◽  
Vol 216 (2) ◽  
pp. 317-330 ◽  
Author(s):  
Oguzhan Atay ◽  
Jan M. Skotheim

Mitogen-activated protein kinase (MAPK) pathways are conserved from yeast to man and regulate a variety of cellular processes, including proliferation and differentiation. Recent developments show how MAPK pathways perform exquisite spatial and temporal signal processing and underscores the importance of studying the dynamics of signaling pathways to understand their physiological response. The importance of dynamic mechanisms that process input signals into graded downstream responses has been demonstrated in the pheromone-induced and osmotic stress–induced MAPK pathways in yeast and in the mammalian extracellular signal-regulated kinase MAPK pathway. Particularly, recent studies in the yeast pheromone response have shown how positive feedback generates switches, negative feedback enables gradient detection, and coherent feedforward regulation underlies cellular memory. More generally, a new wave of quantitative single-cell studies has begun to elucidate how signaling dynamics determine cell physiology and represents a paradigm shift from descriptive to predictive biology.


2007 ◽  
Vol 405 (3) ◽  
pp. 559-568 ◽  
Author(s):  
Joseph Friedman ◽  
Sarah Kraus ◽  
Yirmi Hauptman ◽  
Yoni Schiff ◽  
Rony Seger

The exposure to non-thermal microwave electromagnetic fields generated by mobile phones affects the expression of many proteins. This effect on transcription and protein stability can be mediated by the MAPK (mitogen-activated protein kinase) cascades, which serve as central signalling pathways and govern essentially all stimulated cellular processes. Indeed, long-term exposure of cells to mobile phone irradiation results in the activation of p38 as well as the ERK (extracellular-signal-regulated kinase) MAPKs. In the present study, we have studied the immediate effect of irradiation on the MAPK cascades, and found that ERKs, but not stress-related MAPKs, are rapidly activated in response to various frequencies and intensities. Using signalling inhibitors, we delineated the mechanism that is involved in this activation. We found that the first step is mediated in the plasma membrane by NADH oxidase, which rapidly generates ROS (reactive oxygen species). These ROS then directly stimulate MMPs (matrix metalloproteinases) and allow them to cleave and release Hb-EGF [heparin-binding EGF (epidermal growth factor)]. This secreted factor activates the EGF receptor, which in turn further activates the ERK cascade. Thus this study demonstrates for the first time a detailed molecular mechanism by which electromagnetic irradiation from mobile phones induces the activation of the ERK cascade and thereby induces transcription and other cellular processes.


2007 ◽  
Vol 177 (4) ◽  
pp. 637-645 ◽  
Author(s):  
Satoru Yamasaki ◽  
Kumiko Sakata-Sogawa ◽  
Aiko Hasegawa ◽  
Tomoyuki Suzuki ◽  
Koki Kabu ◽  
...  

Zinc is an essential trace element required for enzymatic activity and for maintaining the conformation of many transcription factors; thus, zinc homeostasis is tightly regulated. Although zinc affects several signaling molecules and may act as a neurotransmitter, it remains unknown whether zinc acts as an intracellular second messenger capable of transducing extracellular stimuli into intracellular signaling events. In this study, we report that the cross-linking of the high affinity immunoglobin E receptor (Fcε receptor I [FcεRI]) induced a release of free zinc from the perinuclear area, including the endoplasmic reticulum in mast cells, a phenomenon we call the zinc wave. The zinc wave was dependent on calcium influx and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activation. The results suggest that the zinc wave is involved in intracellular signaling events, at least in part by modulating the duration and strength of FcεRI-mediated signaling. Collectively, our findings indicate that zinc is a novel intracellular second messenger.


1997 ◽  
Vol 186 (12) ◽  
pp. 1947-1955 ◽  
Author(s):  
Marion Dorsch ◽  
Pang-Dian Fan ◽  
Nika N. Danial ◽  
Paul B. Rothman ◽  
Stephen P. Goff

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.


2015 ◽  
Vol 26 (18) ◽  
pp. 3343-3358 ◽  
Author(s):  
Beverly Errede ◽  
Lior Vered ◽  
Eintou Ford ◽  
Matthew I. Pena ◽  
Timothy C. Elston

Mitogen-activated protein kinase (MAPK) pathways control many cellular processes, including differentiation and proliferation. These pathways commonly activate MAPK isoforms that have redundant or overlapping function. However, recent studies have revealed circumstances in which MAPK isoforms have specialized, nonoverlapping roles in differentiation. The mechanisms that underlie this specialization are not well understood. To address this question, we sought to establish regulatory mechanisms that are unique to the MAPK Fus3 in pheromone-induced mating and chemotropic fate transitions of the budding yeast Saccharomyces cerevisiae. Our investigations reveal a previously unappreciated role for inactive Fus3 as a potent negative regulator of pheromone-induced chemotropism. We show that this inhibitory role is dependent on inactive Fus3 binding to the α-subunit of the heterotrimeric G-protein. Further analysis revealed that the binding of catalytically active Fus3 to the G-protein is required for gradient tracking and serves to suppress cell-to-cell variability between mating and chemotropic fates in a population of pheromone-responding cells.


2021 ◽  
Vol 57 (4) ◽  
pp. 357
Author(s):  
Ido Nur Abdulloh ◽  
Sugiharto Sugiharto ◽  
Purwo Sri Rejeki

Highlight:The differences in intensity physical exercise mechanisms associated with increased irisin secretion in overweight and obese subjects were determined.The secretion of irisin in the right intensity blood on obesity can be reduced because the calories were balanced. Abstract:Physical exercise is a non-pharmacological therapy that can secrete various types of myokines to treat obesity problems. One of the myokines that play a role is irisin. Irisin is a polypeptide hormone with 112 amino acid residues that are synthesized in skeletal muscle after the proteolytic precursor cleavage of fibronectin type III domain-containing protein 5 (FNDC5). The release of irisin in the blood circulation will stimulate the browning process in white fat tissue by inducing the expression of uncoupling protein-1 (UCP-1) through signaling p38 mitogen-activated protein kinase (p38-MAPK) to increase energy expenditure, thermogenesis and reduce fat accumulation. This study described the differences in intensity of physical exercise mechanisms associated with the increased irisin secretion in overweight and obese subjects. This study was designed as a literature review that involved studies from research journals in the last 10 years concerning humans from some databases, such as Science Direct, PubMed, and Google Scholar. This study also discussed the relationship between the intensity of physical exercise and the synthesis, secretion, circulation, and regulation of irisin in preventing obesity.


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