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 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.

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 IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

2005 ◽  
Vol 389 (3) ◽  
pp. 723-729 ◽  
Author(s):  
Bela G. Starkman ◽  
John D. Cravero ◽  
Marcello Delcarlo ◽  
Richard F. Loeser
Keyword(s):  
Mapk Pathway ◽  
Signalling Pathway ◽  
Negative Regulator ◽  
Proteoglycan Synthesis ◽  
Human Articular Cartilage ◽  
Erk Mapk ◽  
Erk Phosphorylation ◽  
Igf I ◽  
Kinase Pathway ◽  
Stimulation Of

The IGF-I (insulin-like growth factor-I) signalling pathway responsible for regulation of proteoglycan synthesis in chondrocytes has not been defined and is the focus of the present study. Chondrocytes isolated from normal human articular cartilage were stimulated with IGF-I in monolayer culture or in suspension in alginate. IGF-I activated members of both the PI3K (phosphoinositide 3-kinase) pathway and the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway. The PI3K inhibitors LY294002 and wortmannin blocked IGF-I-stimulated Akt phosphorylation without blocking ERK phosphorylation and this was associated with complete inhibition of proteoglycan synthesis. A decrease in IGF-I-stimulated proteoglycan synthesis was also observed upon inhibition of mTOR (mammalian target of rapamycin) and p70S6 kinase, both of which are downstream of Akt. The MEK (MAPK/ERK kinase) inhibitors PD98059 and U0126 blocked IGF-I-stimulated ERK phosphorylation but did not block the phosphorylation of Akt and did not decrease proteoglycan synthesis. Instead, in alginate- cultured chondrocytes, the MEK inhibitors increased IGF-I-stimulated proteoglycan synthesis when compared with cells treated with IGF-I alone. This is the first study to demonstrate that IGF-I stimulation of the PI3K signalling pathway is responsible for the ability of IGF-I to increase proteoglycan synthesis. Although IGF-I also activates the ERK/MAPK pathway, ERK activity is not required for proteoglycan synthesis and may serve as a negative regulator.

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 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.

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