Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor (TGF)-beta1 induces fibroblast transdifferentiation to myofibroblasts, a process that requires the involvement of integrin-mediated signaling and focal adhesion kinase (FAK). FAK-related non-kinase (FRNK) is known for its role in inhibiting integrin-mediated cell migration; however, its role in myofibroblast differentiation has not been defined. Here, we report that FRNK abrogates TGF-beta1-induced myofibroblast differentiation in vitro and in vivo. TGF-beta1 can induce alpha-smooth muscle actin (alpha-SMA) expression in the presence or absence of FAK; however, TGF-beta1-induced alpha-SMA expression is reduced (approximately 73%) in FAK-deficient fibroblasts. Although both ERK and p38 MAPK activation is required for maximal TGF-beta1-induced alpha-SMA expression, ERK is the major signaling intermediate in cells that express FAK. In contrast, p38 MAPK is the dominant mediator of TGF-beta1-induced alpha-SMA expression in FAK-deficient cells. FRNK overexpression blocks TGF-beta1-induced ERK or p38 MAPK activation in the presence, and surprisingly, in the absence of FAK. The loss of FRNK was tested in vivo during experimentally induced pulmonary fibrosis in mice. FRNK knock-out mice have a greater increase in alpha-SMA-expressing cells in response to a pulmonary fibrotic stimulus in vivo, as compared with congenic wild type mice. This is the first time that FRNK loss has been shown to modify the pathobiology in any animal disease model. Together, the data demonstrate that FRNK negatively regulates myofibroblast differentiation in vitro and in vivo. These data further suggest that modulation FRNK expression may be a novel avenue for therapeutic intervention in tissue fibrosis.
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PMID:Focal adhesion kinase (FAK)-related non-kinase inhibits myofibroblast differentiation through differential MAPK activation in a FAK-dependent manner. 1866 33

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare inflammatory tumor-like lesion composed of vascular nodules and non-neoplastic stroma including spindle cells and inflammatory cells. The focus of our study was on the stromal proliferating process in SANT. Nine cases of SANT were examined. All cases showed alpha-smooth muscle actin (alpha-SMA) and vimentin on the spindle cells but not CD21, CD31, CD34, CD68, desmin, S100, human herpes virus-8, or anaplastic lymphoma kinase-1. In one case, 20-30% of the myofibroblasts in Epstein-Barr-virus (EBV)-positive spindle cells were detected using double-labeling immunohistochemistry for alpha-SMA and EBV-encoded small RNA in situ hybridization. A quantitative analysis of IgG and IgG4-positive plasma cells (pPCs) in SANT was performed. The median densities of IgG-pPCs and IgG4-pPCs in SANT were approximately four-fold and 13-fold higher than those in the normal spleens, respectively. In addition, there was a statistically significant increase of IgG4/IgG-pPCs ratio in SANT in comparison to the control specimens. In conclusion, the fibrogenesis in a subset of SANT may be associated with EBV-infected myofibroblasts in an overlapping immune reaction indicated by the presence of infiltrating IgG4-pPCs. Further investigation is needed to elucidate the association between SANT and IgG4-related sclerosing disease.
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PMID:Detection of Epstein-Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular transformation of the spleen. 1869 8

The author reports a rare case of primary large cystic extragastrointestinal stromal tumor (eGIST) of the transverse mesocolon with genetic analyses of the c-kit and platelet-derived growth factor receptor-alpha (PDGFRA) genes. A 78-year-old man was found to have a large cystic tumor in the abdomen, and the tumor was resected. Grossly, the tumor was located in the transverse mesocolon, and cystic. Microscopically, the tumor consisted of epithelioid cells with atypia. Mitotic figures were noted in five of 50 high power fields. Immunohistochemically, the tumor cells were positive for KIT, CD34, PDGFRA, and vimentin, but negative for cytokeratins, neuron specific enolase, desmin, S100 protein, alpha-smooth muscle actin, p53 protein, HMB45, CD68, CEA, factor VIII-related antigen, chromogranin, and synaptophysin. Ki67 labeling was 5%. Genetically, the tumor showed a point mutation (GAC --> GTC) at codon 842 of exon 18 of the PDGFRA gene. Exon 12 of the PDGFRA gene and exons 9, 11, 13, and 17 of the c-kit gene showed no mutations. No recurrence is noted 3 years after the operation. This case shows that eGIST may occur in the transverse mesocolon.
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PMID:Primary extragastrointestinal stromal tumor of the transverse mesocolon without c-kit mutations but with PDGFRA mutations. 1877 14

The author reports a very rare case of a gastrointestinal stromal tumor in the uterus. A 74-year-old woman was admitted to our hospital because of pelvic pain. Imaging modalities showed a large tumor of the posterior aspect of the uterus, and enucleation was performed. The tumor was attached to the posterior uterus, similar to subserosal leiomyoma. No attachment to the gastrointestinal organs was recognized. The tumor was soft, tan, and measured 13 x 15 x 12 cm. The tumor consisted of cellular spindle cells with focal necrotic areas. Mitotic figures were noted in 3 of 50 high-power fields. The tumor cells were positive for KIT, CD34, platelet-derived growth factor receptor alpha, and vimentin, but negative for alpha-smooth muscle actin, S100 protein, p53 protein, HMB45, and desmin. Ki-67 labeling was 3%. Five normal uteruses used as controls showed KIT-positive Cajal-like mesenchymal cell scattering in the myometrium. Genetic analyses of the c-kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor alpha gene (exons 12 and 18) revealed a point mutation at codon 559 (GTT-->GAT) of exon 11 of the c-kit gene. Other exons showed no abnormalities. This case shows that gastrointestinal stromal tumor may occur in the uterus.
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PMID:Gastrointestinal stromal tumor of the uterus: a case report with genetic analyses of c-kit and PDGFRA genes. 1904 11

The author reports herein two cases of ductal adenoma of the breast with an emphasis on immunohistochemistry. Both cases (patient 1, 58-year-old woman; patient 2, 78-year-old woman) were clinically suspected as carcinoma, and core biopsies were 'indeterminate' or 'suspicious for malignancy'. Excisional biopsy and wide excision were performed. Histologically, both cases were ductal adenomas composed of ductal epithelial cells and myoepithelial cells. Patient 1 had extensive apocrine metaplasia. Immunohistochemically, myoepithelial cells were noted in both cases; cytokeratin (CK) 14 and p63 were the most reliable myoepithelial markers, followed by CD10, alpha-smooth muscle actin and S100 protein. CK profile was as follows: positive expression of CK5/6, CK18, CK19, and high-molecular-weight CK, and negative expression of CK20. This CK profile was the same as that of non-tumorous ducts, suggesting that the CK profile does not alter in tumorigenesis. The tumor cells expressed p53 protein (case 1, positive cell percentage 5%; case 2, 7%), c-erbB2 (HER2/neu, 76%, 64%), CEA (5%, 0%), estrogen receptor (33%, 84%), but were negative for progesterone receptor. Ki-67 labeling was 5% and 3%, respectively. MUC apomucin expression was as follows: MUC1, 92%, 100%; MUC2, 0%, 0%; MUC5AC, 0%, 0%; and MUC6, 5%, 0%. Non-tumorous ducts expressed MUC1, but were negative for MUC2, MUC5AC and MUC6.
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PMID:Ductal adenoma of the breast: immunohistochemistry of two cases. 1906 57

The author reports a very rare case of sporadic primary multiple extragastrointestinal stromal tumors (EGISTs) of the omentum associated with different mutations of the exon 11 of the c-kit gene in a 75-year-old man with gastric cancer. During an operation for the cancer, two solid tumors (10 mm and 8 mm) were found in the omentum. Both tumors consisted of cellular spindle cells. Mitotic figures were two and three per 50 high power fields. The tumor cells were positive for KIT, CD34 and vimentin, but negative for desmin, S100 protein, alpha-smooth muscle actin and p53 protein. Ki67 labeling was 2% and 3%. The larger EGIST showed a deletion of codons 552-558 of exon 11 of the c-kit gene, while the smaller EGIST had a point mutation at codon 559 (GTT-->GAT) in exon 11 of the c-kit gene. Exons 9, 13, and 17 of the c-kit gene, and exons 12 and 18 of the platelet derived growth factor receptor alpha genes showed no mutations. The case shows that sporadic multiple EGISTs can occur in the omentum.
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PMID:Primary multiple extragastrointestinal stromal tumors of the omentum with different mutations of c-kit gene. 1908 44

Liver fibrosis due to hepatic stellate cell (HSC) activation represents a common response to chronic liver injury. PTK787/ZK222584 (PTK/ZK) is a pan-VEGFR tyrosine kinase inhibitor. The aim of this study was to examine the effect of PTK/ZK in liver fibrosis. In primary HSCs, PTK/ZK inhibited the expression of alpha-smooth muscle actin (alpha-SMA), collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as cell proliferation, migration and actin filament formation. PTK/ZK-induced apoptosis of HSCs, which was correlated with increased caspase-3 activation and suppressed Bcl-2 expression. PTK/ZK also induced cell cycle arrest, accompanied by increasing the expression of p27(Kip1) and downregulation of cyclin D1 and cyclin E. PTK/ZK significantly inhibited vascular endothelial growth factor (VEGF) expression, as well as VEGF-simulated cell proliferation and phosphorylation of Akt in activated HSCs. In a murine fibrotic liver, PTK/ZK attenuated collagen deposition and alpha-SMA expression in carbon tetrachloride-induced fibrosis in both a 'prevention' and 'treatment' dosing scheme. These beneficial effects were associated with reduced phosphorylation of Akt and suppressed mRNA expression of procollagen-(I), TIMP-1, matrix metalloproteinase-9 and CD31. These findings provide novel insights into the potential value of blocking VEGF signaling by a small molecule tyrosine kinase inhibitor in treating hepatic fibrosis.
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PMID:PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. 1911 84

Reported herein is a gastrointestinal stromal tumor (GIST) that exhibited a hemangiopericytoma (HPC)-like histological pattern. Such a morphological variant of GIST has not been described previously. A 57-year-old woman presented with bloody stools. On upper digestive tract endoscopy a submucosal tumor of diameter 2 cm was detected at the duodenal bulb, and enucleated. Grossly, the tumor was well-circumscribed, grayish to whitish, and solid, and its central portion was ulcerated. Histology indicated round to fusiform tumor cells that had proliferated around branching vessels that had a staghorn configuration. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin and KIT; partially positive for CD34 and muscle actin; and negative for alpha-smooth muscle actin. On mutation analysis a 42 bp deletion was found from codons 560 to 573 of exon 11 of the KIT gene, which is a mutational hot spot of GIST. In diagnosis of gastrointestinal tract tumors with an HPC-like histological pattern, pathologists should consider the possibility of GIST.
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PMID:Gastrointestinal stromal tumor in the duodenum exhibiting hemangiopericytoma-like histological pattern. 1915 63

CD34 is frequently used as a marker of adipose-derived stem/stromal/progenitor cells (ASCs). However, CD34 expression in human ASCs (hASCs) decreases over time in culture, and the implications of this remain unclear. In this study, we sorted shortly-cultured hASCs into CD34+ and CD34- fractions and compared their biological functions. Results indicated that CD34+ hASCs were more proliferative and had a greater ability to form colonies. In contrast, CD34- cells showed a greater ability for differentiation into adipogenic and osteogenic lineages. Both CD34+ and CD34- cells showed similar abilities in migration and capillary formation in response to growth factors. Expression levels of endothelial progenitor markers (Flk-1, FLT1, and Tie-2) were higher in CD34+ cells, whereas those of pericyte markers (CD146, NG2, and alpha-smooth muscle actin) were higher in CD34- cells. Both CD34+ and CD34- cells showed similar expression levels of vascular endothelial growth factor and hepatocyte growth factor, although hypoxia affected the expression levels. Together these results suggest that CD34 expression in hASCs may correlate with replicative capacity, differentiation potentials, expression profiles of angiogenesis-related genes, and immaturity or stemness of the cells. Loss of CD34 expression may be related to the physiological process of commitment and/or differentiation from immature status into specific lineages such as adipose, bone, or smooth muscle.
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PMID:Functional implications of CD34 expression in human adipose-derived stem/progenitor cells. 1922 22

Prostanoid metabolites are key mediators in inflammatory responses, and accumulating evidence suggests that mesenchymal stem cells (MSCs) can be recruited to injured or inflamed tissues. In the present study, we investigated whether prostanoid metabolites can regulate migration, proliferation, and differentiation potentials of MSCs. We demonstrated herein that the stable thromboxane A(2) (Tx(2)) mimetic U46619 strongly stimulated migration and proliferation of human adipose tissue-derived MSCs (hADSCs). Furthermore, U46619 treatment increased expression of alpha-smooth muscle actin (alpha-SMA), a smooth muscle marker, in hADSCs, suggesting differentiation of hADSCs into smooth muscle-like cells. U46619 activated ERK and p38 MAPK, and pretreatment of the cells with the MEK inhibitor U0126 or the p38 MAPK inhibitor SB202190 abrogated the U46619-induced migration, proliferation, and alpha-SMA expression. These results suggest that TxA2 plays a key role in the migration, proliferation, and differentiation of hADSCs into smooth muscle-like cells through signaling mechanisms involving ERK and p38 MAPK.
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PMID:Thromboxane A(2) modulates migration, proliferation, and differentiation of adipose tissue-derived mesenchymal stem cells. 1928 96


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