scholarly journals An Effective Model of HL-60 Differentiation

2015 ◽  
Author(s):  
Ryan Tasseff ◽  
Holly A Jensen ◽  
Johanna Congleton ◽  
Andrew Yen ◽  
Jeffrey D Varner
Keyword(s):  
Cell Fate ◽  
Positive Feedback ◽  
Effective Model ◽  
Mitogen Activated Protein Kinase ◽  
Model Parameters ◽  
Nucleotide Exchange ◽  
Induced Differentiation ◽  
All Trans Retinoic Acid ◽  
Architectural Feature ◽  
Mitogen Activated Protein

We present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes a key architectural feature of ATRA-induced differen- tiation, positive feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. The model, which was developed by integrating logical rules with kinetic model- ing, was significantly smaller than previous models. However, despite its simplicity, it captured key features of ATRA induced differentiation of HL-60 cells. We identified an ensemble of effec- tive model parameters using measurements taken from ATRA- induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA- induced bistability. These findings, combined with other literature evidence, suggest that positive feedback is central to a diversity of cell fate programs.

scholarly journals An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program

2017 ◽  
Author(s):  
Ryan Tasseff ◽  
Holly A. Jensen ◽  
Johanna Congleton ◽  
Wei Dai ◽  
Katharine V. Rogers ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Retinoic Acid ◽  
Cell Fate ◽  
Ppar Gamma ◽  
Effective Model ◽  
Mitogen Activated Protein Kinase ◽  
Model Parameters ◽  
Nucleotide Exchange ◽  
Differentiation Markers ◽  
Induced Differentiation

ABSTRACTIn this study, we present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes reinforcing feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. We decomposed the effective model into three modules; a signal initiation module that sensed and transformed an ATRA signal into program activation signals; a signal integration module that controlled the expression of upstream transcription factors; and a phenotype module which encoded the expression of functional differentiation markers from the ATRA-inducible transcription factors. We identified an ensemble of effective model parameters using measurements taken from ATRA-induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA-induced bistability. Additionally, the model captured intermediate and phenotypic gene expression data. Knockout analysis suggested Gfi-1 and PPAR$[gamma] were critical to the ATRA-induced differentiation program. These findings, combined with other literature evidence, suggested that reinforcing feedback is central to hyperactive signaling in a diversity of cell fate programs.

scholarly journals Constitutive Activation of Mitogen-activated Protein Kinase Kinase (MEK1) in Ileal Enterocytes Leads to Dysplasia and a Predisposition to Cancer

2021 ◽  
Author(s):  
Benjamin L. Shneider ◽  
Nahir Cortes-Santiago ◽  
Deborah A. Schady ◽  
Swapna Krishnamoorthy ◽  
Sundararajah Thevananther ◽  
...  
Keyword(s):  
Body Weight ◽  
Protein Kinase ◽  
Cell Fate ◽  
Dose Dependence ◽  
Mitogen Activated Protein Kinase ◽  
Proteomic Profiling ◽  
Invasive Adenocarcinoma ◽  
Reduced Body ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

Activation of Mitogen-activated protein kinases (MAPKs) is a key factor in the pathogenesis of cancer, although the specific role of mitogen-activated protein kinase kinase (MEK1) is not well understood. Villin promoter driven cre expression was used to excise a floxed stop cassette from a phosphomimetically constitutively activated MEK1 (caMEK1) expression construct in the intestine of C57BL/6 mice. Zygosity status of caMEK1 afforded assessment of the dose dependence of the effect. The expected mendelian distribution of genotypes and sex was observed in 443 progenies. Between 21 and 63 days of life caMEK1 had no effect on body weight in male mice, but reduced body weight in female mice homozygous for caMEK1. At 10 weeks of age, the ileum of caMEK1 expressing mice was characterized by the finding of dysplasia and profound changes in overall architecture. Paneth cells were nearly absent in caMEK1 homozygotes. Targeted proteomic profiling via reverse phase protein array analyses with confirmatory western blotting revealed significant changes in protein and phosphoprotein expression including up-regulation of proteins downstream of MEK1, associated with enhanced markers of proliferation, diminished apoptosis, alterations in cell-fate determination, cell-cell interactions and tight junctions. Long-term viability of caMEK1 homozygous mice was reduced with no survival beyond one year. Invasive adenocarcinoma developed in three of ten older mice (15 [homozygous], 26 [homozygous] and 35 weeks [heterozygous] of age). Expression of caMEK1 in enterocytes leads to marked derangements in the intestinal epithelium, which is associated with a predisposition to the development of invasive cancer.

scholarly journals Understanding MAPK Signaling Pathways in Apoptosis

2020 ◽  
Vol 21 (7) ◽  
pp. 2346 ◽  
Author(s):  
Jicheng Yue ◽  
José M. López
Keyword(s):  
Signaling Pathways ◽  
Positive Feedback ◽  
Cell Model ◽  
Mapk Signaling ◽  
Feedback Loops ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Mechanisms ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Mapk Signaling Pathways

MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.

scholarly journals Interaction of Rac Exchange Factors Tiam1 and Ras-GRF1 with a Scaffold for the p38 Mitogen-Activated Protein Kinase Cascade

2002 ◽  
Vol 22 (12) ◽  
pp. 4073-4085 ◽  
Author(s):  
Rachel J. Buchsbaum ◽  
Beth A. Connolly ◽  
Larry A. Feig
Keyword(s):  
Map Kinase ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Nucleotide Exchange ◽  
Rac Gtpase ◽  
Signaling Specificity ◽  
Map Kinase Cascade ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
In Cells

ABSTRACT Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.

scholarly journals Ras isoforms: signaling specificities in CD40 pathway

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Arathi Nair ◽  
Sushmita Chakraborty ◽  
Late Anirban Banerji ◽  
Ankita Srivastava ◽  
Charudutta Navare ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Phosphatidyl Inositol ◽  
Mitogen Activated Protein Kinase ◽  
High Dose ◽  
Nucleotide Exchange ◽  
Ras Activation ◽  
Mitogen Activated Protein ◽  
Cd40 Stimulation ◽  
Ras Isoforms ◽  
Deficient Mice

Abstract Background Ras are small cellular GTPases which regulate diverse cellular processes. It has three isoforms: H-Ras, K-Ras, and N-Ras. Owing to the N-terminus (1–165 residues) sequence homology these isoforms were thought to be functionally redundant. However, only K-Ras-deficient mice but not H-Ras- and N-Ras-deficient mice show embryonic lethality. Similarly, mutations in a given Ras isoform are associated with a particular type of cancer. Moreover, we have previously reported that Ras isoforms perform unique functions in Leishmania major infection. Thus, Ras isoforms are implicated to have signaling and functional specificity but the mechanism remains to be elucidated. Result Using CD40 as a model receptor, we showed that depending on the strength of signaling, specific Ras isoforms are activated. Weak CD40 signal activates N-Ras, whereas strong signal activates H-Ras and K-Ras. Additionally, we showed that suppression of N-Ras expression reduced CD40-induced extracellular signal–regulated kinase-1/2 (ERK-1/2) activation and Interleukin (IL)-10 production; whereas suppression of H-Ras or K-Ras reduced CD40-induced p38 mitogen-activated protein kinase (p38MAPK) activation and IL-12 production. Furthermore, we showed that Ras isoforms have activator (GEF) specificity as weak CD40 signal-activated N-Ras requires Sos-1/2 whereas strong CD40 signal-activated H-Ras/K-Ras requires Ras-GRP as the guanine-nucleotide exchange factor (GEF) inducing ERK-1/2- or p38MAPK-mediated IL-10 or IL-12 productions, respectively, in macrophages. Silencing of syk reduced CD40-induced N-Ras activation but silencing of lyn inhibited H-Ras and K-Ras activation. In CD40 signaling, Ras isoforms also showed effector specificity; while H-Ras and K-Ras showed specificity for phosphatidyl inositol-3 kinase activation at high dose of CD40 stimulation, N-Ras primarily associated with Raf-1 at low dose of CD40 stimulation. Moreover, fractal analysis showed that functional site surface roughness for H-Ras (SurfaceFD = 2.39) and K-Ras (SurfaceFD = 2.39) are similar but significantly different from N-Ras (SurfaceFD = 2.25). Conclusion The activator and effector specificities of Ras isoforms in CD40 signaling indicated their differential involvement in CD40 pathway and in maintaining the reciprocity. Our observations reveal Ras-regulated signaling outcome and its potential for developing Ras isoform-targeted immunotherapy and prophylaxis. Graphical abstract

scholarly journals Semaphorin 4D activates the MAPK pathway downstream of plexin-B1

2006 ◽  
Vol 394 (2) ◽  
pp. 459-464 ◽  
Author(s):  
Jennifer Aurandt ◽  
Weiquan Li ◽  
Kun-Liang Guan
Keyword(s):  
Nervous System ◽  
Mapk Pathway ◽  
Large Family ◽  
Cellular Systems ◽  
Mitogen Activated Protein Kinase ◽  
Nucleotide Exchange ◽  
Semaphorin 4D ◽  
C Terminus ◽  
Nucleotide Exchange Factor ◽  
Mitogen Activated Protein

Semaphorins are a large family of transmembrane and secreted proteins that signal primarily through the receptor plexin. Semaphorins have been characterized in the nervous system as axon guidance cues; however, they have also been shown to control development of other cellular systems such as the vasculature and lungs. As the role of semaphorins outside of the nervous system has broadened, so has elucidation of the intracellular signalling pathways they initiate. Previously, we and others have shown that plexin-B1 activates RhoA through the binding and activation of RhoGEF (guanine nucleotide-exchange factor)/LARG (leukaemia-associated RhoGEF) in response to semaphorin 4D stimulation. In the present study, we show that semaphorin 4D activates the MAPK (mitogen-activated protein kinase) pathway. We have found that the mechanism of activation requires the C-terminus of plexin-B1 and the activation of RhoA.

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