scholarly journals The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis

2019 ◽  
Vol 20 (8) ◽  
pp. 1803 ◽  
Author(s):  
Jung-Min Kim ◽  
Yeon-Suk Yang ◽  
Kwang Hwan Park ◽  
Hwanhee Oh ◽  
Matthew B. Greenblatt ◽  
...  
Keyword(s):  
Bone Formation ◽  
Protein Kinases ◽  
Mapk Pathway ◽  
Wide Spectrum ◽  
Skeletal Development ◽  
Neurofibromatosis Type ◽  
Cleidocranial Dysplasia ◽  
Erk Activation ◽  
Erk Mapk ◽  
Adult Mice

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1OsxMek2−/−), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1Osx-ERTMek2−/−) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and β-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation.

scholarly journals Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder

2021 ◽  
Author(s):  
Shinsuke Oda ◽  
Masayoshi Fujisawa ◽  
Li Chunning ◽  
Toshihiro Ito ◽  
Takahiro Yamaguchi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Cancer Progression ◽  
Mapk Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Ki67 Index ◽  
Erk Activation ◽  
Non Invasive ◽  
Erk Mapk

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 negatively regulates cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

Stromal inhibition of megakaryocytic differentiation is associated with blockade of sustained Rap1 activation

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1744-1751 ◽  
Author(s):  
Lorrie L. Delehanty ◽  
Michael Mogass ◽  
Sara L. Gonias ◽  
Frederick K. Racke ◽  
Brian Johnstone ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Control Point ◽  
Resistant Mutant ◽  
Nucleotide Exchange ◽  
Contact Activation ◽  
Erk Activation ◽  
Megakaryocytic Differentiation ◽  
Erk Mapk ◽  
Rap1 Activation

Coculture with stromal cells tends to maintain normal hematopoietic progenitors and their leukemic counterparts in an undifferentiated, proliferative state. An example of this effect is seen with megakaryocytic differentiation, wherein stromal contact renders many cell types refractory to potent induction stimuli. This inhibitory effect of stroma on megakaryocytic differentiation correlates with a blockade within hematopoietic cells of protein kinase C-ε (PKC-ε) up-regulation and of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase activation, both of which have been implicated in promoting megakaryocytic differentiation. In this study K562ΔRafER.5 cells, expressing an estradiol-responsive mutant of the protein kinase Raf-1, were used to determine the relevance and stage of ERK/MAPK pathway blockade by stromal contact. Activation of ΔRafER by estradiol overrode stromal blockade of megakaryocytic differentiation, implicating the proximal stage of the ERK/MAPK pathway as a relevant control point. Because stromal contact blocked delayed but not early ERK activation, the small guanosine triphosphatase (GTPase) Rap1 was considered as a candidate inhibitory target. Activation assays confirmed that Rap1 underwent sustained activation as a result of megakaryocytic induction, as previously described. As with ERK activation, stromal contact selectively blocked delayed but not early Rap1 activation, having no effect on Ras activation. Enforced expression of either wild-type Rap1 or the GTPase (GAP) resistant mutant Rap1 V12 failed to override stromal inhibition, suggesting that the inhibitory mechanism does not involve GAP up-regulation but rather may target upstream guanine nucleotide exchange factor (GEF) complexes. Accordingly, coimmunoprecipitation demonstrated stromally induced alterations in a protein complex associated with c-Cbl, a scaffolding factor for Rap1-GEF complexes.

scholarly journals Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0254289
Author(s):  
Shinsuke Oda ◽  
Masayoshi Fujisawa ◽  
Li Chunning ◽  
Toshihiro Ito ◽  
Takahiro Yamaguchi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Cancer Progression ◽  
Mapk Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Ki67 Index ◽  
Erk Activation ◽  
Non Invasive ◽  
Erk Mapk

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

scholarly journals Expression of Spred2 in the Urothelial Tumorigenesis of the Urinary Bladder

2021 ◽  
Author(s):  
Shinsuke Oda ◽  
Masayoshi Fujisawa ◽  
Li Chunning ◽  
Toshihiro Ito ◽  
Takahiro Yamaguchi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Cancer Progression ◽  
Mapk Pathway ◽  
Negative Regulator ◽  
Ki67 Index ◽  
Erk Activation ◽  
Non Invasive ◽  
Erk Mapk ◽  
In Cis

Abstract Aberrant activation of the Ras/Raf/ERK-MAPK pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. Here, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and a cell proliferation marker Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC) and carcinoma in situ (CIS), and the expression was decreased in invasive urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 negatively regulates cancer progression in non-invasive papillary carcinoma possibly through inhibiting Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in CIS and IUC. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

scholarly journals Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway

2020 ◽  
Author(s):  
Taryn E. Gillies ◽  
Michael Pargett ◽  
Jillian M. Silva ◽  
Carolyn Teragawa ◽  
Frank McCormick ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Erk Activation ◽  
Ras Mutations ◽  
Activating Mutations ◽  
Erk Mapk ◽  
Erk Activity

AbstractActivating mutations in RAS are present in ∼30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo. Rationally targeting the kinase activity of this pathway requires clarification of the quantitative effects of RAS mutations. Here, we use live-cell imaging in cell lines expressing only one RAS isoform to quantify ERK activity with a new level of accuracy. We find that despite large differences in their biochemical activity, mutant KRAS isoforms within cells have similar ranges of ERK output. We identify roles for pathway-level effects, including variation in feedback strength and feedforward modulation of phosphatase activity, that act to rescale pathway sensitivity independent of expression level, ultimately resisting changes in the dynamic range of ERK activity while preserving responsiveness to growth factor stimuli. Our results reconcile seemingly inconsistent reports within the literature and imply that the initial signaling changes induced by RAS mutations in oncogenesis are subtle.

Asparanin A inhibits cell migration and invasion in human endometrial cancer via Ras/ERK/MAPK pathway

2021 ◽  
Vol 150 ◽  
pp. 112036 ◽  
Author(s):  
Fan Zhang ◽  
Zhi-Jing Ni ◽  
Lei Ye ◽  
Yuan-Yuan Zhang ◽  
Kiran Thakur ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Migration ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Erk Mapk

Dissociation of bone resorption and bone formation in adult mice transplanted with OC/OC hematopoietic stem cells

Bone ◽  
2010 ◽  
Vol 47 ◽  
pp. S139
Author(s):  
C. Flores ◽  
C.S. Thudium ◽  
G. Langenbach ◽  
M. Brüel ◽  
N.A. Sims ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Resorption ◽  
Bone Formation ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Adult Mice

scholarly journals The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway

2015 ◽  
Vol 35 (7) ◽  
pp. 3190-3200 ◽  
Author(s):  
J. Pucilowska ◽  
J. Vithayathil ◽  
E. J. Tavares ◽  
C. Kelly ◽  
J. C. Karlo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Erk Mapk ◽  
Cortical Progenitor

scholarly journals Differential role of SIRT1/MAPK pathway during cerebral ischemia in rats and humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sireesh Kumar Teertam ◽  
Phanithi Prakash Babu
Keyword(s):  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Mapk Pathway ◽  
Protective Role ◽  
Akt Signaling ◽  
Sirtuin 1 ◽  
Neurological Dysfunction ◽  
Dependent Manner ◽  
Erk Mapk

AbstractCerebral ischemia (CI) is a severe cause of neurological dysfunction and mortality. Sirtuin-1 (Silent information regulator family protein 1, SIRT1), an oxidized nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, plays an important role in protection against several neurodegenerative disorders. The present study aims to investigate the protective role of SIRT1 after CI in experimental young and aged rats and humans. Also, the study examines the possible regulatory mechanisms of neuronal death in CI settings. Immunoblotting and immunohistochemistry were used to evaluate changes in the expression of SIRT1, JNK/ERK/MAPK/AKT signaling, and pro-apoptotic caspase-3 in experimental rats and CI patients. The study findings demonstrated that, in aged experimental rats, SIRT1 activation positively influenced JNK and ERK phosphorylation and modulated neuronal survival in AKT-dependent manner. Further, the protection conferred by SIRT1 was effectively reversed by JNK inhibition and increased pro-apoptotic caspase-3 expression. In young experimental rats, SIRT1 activation decreased the phosphorylation of stress-induced JNK, ERK, caspase-3, and increased the phosphorylation of AKT after CI. Inhibition of SIRT1 reversed the protective effect of resveratrol. More importantly, in human patients, SIRT1 expression, phosphorylation of JNK/ERK/MAPK/AKT signaling and caspase-3 were up-regulated. In conclusion, SIRT1 could possibly be involved in the modulation of JNK/ERK/MAPK/AKT signaling pathway in experimental rats and humans after CI.

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