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https://www.readbyqxmd.com/read/28820389/hippo-pathway-brief-overview-of-its-relevance-in-cancer
#1
A L Zygulska, K Krzemieniecki, P Pierzchalski
The Hippo pathway is the major regulator of organ growth and proliferation. Described initially in Drosophila, it is now recognized as one of the most conserved molecular pathways in all metazoan. Recent studies have revealed the Hippo signalling pathway might contribute to tumorigenesis and cancer development. The core components of the Hippo pathway include the mammalian sterile 20-like kinases (MSTs), large tumour suppressor kinases (LATSs), the adaptor proteins Salvador homologue 1 (SAV1, also called WW45) and Mps One Binder kinase activator proteins...
June 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28815883/wwc2-is-an-independent-prognostic-factor-and-prevents-invasion-via-hippo-signalling-in-hepatocellular-carcinoma
#2
Yijun Zhang, Shumei Yan, Jiewei Chen, Caixia Gan, Dong Chen, Yan Li, Jiahuai Wen, Joachim Kremerskothen, Shilu Chen, Jiangbo Zhang, Yun Cao
WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes-associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC)...
August 16, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28757477/the-roles-and-mechanisms-of-the-hippo-yap-signaling-pathway-in-the-nervous-system
#3
Bao Xiaomei, He Qing, Wang Ying, Huang Zhihui, Yuan Zengqiang
The Hippo signaling pathway, consisting of a highly conserved kinase cascade and downstream transcription co-activators YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif), plays a key role in tissue homeostasis and organ size control by regulating the proliferation, differentiation and apoptosis of cells. During normal development, the precise control of neural cell numbers and spatial distributions of these neural cells is important for brain development. Recent studies have shown that the Hippo/YAP signaling pathway is actively involved in the self-renewal of neural stem cells, proliferation of neural progenitor cells, differentiation and activation of glial cells, and myelination of glial cells as well as in the development of neurological diseases...
July 20, 2017: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/28757470/molecular-mechanisms-of-the-mammalian-hippo-signaling-pathway
#4
Ji Xinyan, Zhong Guoxuan, Zhao Bin
The Hippo pathway plays an evolutionarily conserved fundamental role in controlling organ size in multicellular organisms. Importantly, evidence from studies of patient samples and mouse models clearly indicates that deregulation of the Hippo signaling pathway plays a crucial role in the initiation and progression of many different types of human cancers. The Hippo signaling pathway is regulated by various stimuli, such as mechanical stress, G-protein coupled receptor signaling, and cellular energy status. When activated, the Hippo kinase cascade phosphorylates and inhibits the transcription co-activator YAP (Yes-associated protein), and its paralog TAZ (transcriptional coactivator with PDZ-binding motif), resulting in their cytoplasmic retention and degradation...
July 20, 2017: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/28724435/ww-domain-binding-protein-2-an-adaptor-protein-closely-linked-to-the-development-of-breast-cancer
#5
REVIEW
Shuai Chen, Han Wang, Yu-Fan Huang, Ming-Li Li, Jiang-Hong Cheng, Peng Hu, Chuan-Hui Lu, Ya Zhang, Na Liu, Chi-Meng Tzeng, Zhi-Ming Zhang
The WW domain is composed of 38 to 40 semi-conserved amino acids shared with structural, regulatory, and signaling proteins. WW domain-binding protein 2 (WBP2), as a binding partner of WW domain protein, interacts with several WW-domain-containing proteins, such as Yes kinase-associated protein (Yap), paired box gene 8 (Pax8), WW-domain-containing transcription regulator protein 1 (TAZ), and WW-domain-containing oxidoreductase (WWOX) through its PPxY motifs within C-terminal region, and further triggers the downstream signaling pathway in vitro and in vivo...
July 19, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28718435/agrin-to-yap-in-cancer-and-neuromuscular-junctions
#6
Wen-Cheng Xiong, Lin Mei
Agrin is utilized by motor neurons to stimulate the LRP4-MuSK receptor in muscles for neuromuscular junction (NMJ) formation. Recent studies of cancer have identified novel functions of the low-density lipoprotein receptor-related protein 4-muscle-specific kinase (LRP4-MuSK) pathway. Agrin may act as a mechanotransduction signal in the extracellular matrix (ECM) to coordinate the cross-talk between the LRP4-MuSK pathway and integrin-focal adhesion pathway. Ensuing Yes-associated protein (YAP) activation promotes hepatocellular carcinoma (HCC)...
April 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28715434/engineered-extracellular-matrices-with-controlled-mechanics-modulate-renal-proximal-tubular-cell-epithelialization
#7
Jeffrey A Beamish, Evan Chen, Andrew J Putnam
Acute kidney injury (AKI) is common and associated with significant morbidity and mortality. Recovery from many forms of AKI involves the proliferation of renal proximal tubular epithelial cells (RPTECs), but the influence of the microenvironment in which this recovery occurs remains poorly understood. Here we report the development of a poly(ethylene glycol) (PEG) hydrogel platform to study the influence of substrate mechanical properties on the proliferation of human RPTECs as a model for recovery from AKI...
2017: PloS One
https://www.readbyqxmd.com/read/28680534/nsclc-depend-upon-yap-expression-and-nuclear-localization-after-acquiring-resistance-to-egfr-inhibitors
#8
Marc McGowan, Lilach Kleinberg, Ann Rita Halvorsen, Åslaug Helland, Odd Terje Brustugun
Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes...
March 2017: Genes & Cancer
https://www.readbyqxmd.com/read/28677804/mapk-and-hippo-signaling-pathways-crosstalk-via-the-raf-1-mst-2-interaction-in-malignant-melanoma
#9
Ruizheng Feng, Junsheng Gong, Lina Wu, Lei Wang, Baolin Zhang, Gang Liang, Huixia Zheng, Hong Xiao
The aim of the present study was to expound on the interactions between the mitogen-activated protein kinase (MAPK) and Hippo pathway members, and to further elucidate the molecular mechanisms of melanoma tumorigenesis. Four melanoma cell lines (C32, HS695T, SK-MEL-28 and A375) were used in the present study. Western blotting was used to assess the expression levels of the MAPK and Hippo pathway effector proteins: rapidly accelerated fibrosarcoma-1 proto-oncogene, serine/threonine kinase (RAF-1); serine/threonine kinase 3 (STK3; also known as MST-2); yes-associated protein (YAP); and tafazzin (TAZ)...
June 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28651433/profile-qsar-2-0-kinase-virtual-screening-accuracy-comparable-to-4-concentration-ic50s-for-realistically-novel-compounds
#10
Eric Martin, Valery R Polyakov, Li Tian, Rolando Perez
While conventional random forest regression (RFR) virtual screening models appear to have excellent accuracy on random held-out test sets, they prove lacking in actual practice. Analysis of 18 historical virtual screens showed that random test sets are far more similar to their training sets than are the compounds project teams actually order. A new, cluster-based "realistic" training/test set split, which mirrors the chemical novelty of real-life virtual screens, recapitulates the poor predictive power of RFR models in real projects...
June 26, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28634071/the-novel-yap-target-gene-sgk1-upregulates-taz-activity-by-blocking-gsk3%C3%AE-mediated-taz-destabilization
#11
Geon Yoo, Tackhoon Kim, Chaeuk Chung, Deog-Su Hwang, Dae-Sik Lim
YAP (Yes-associated protein) and TAZ (transcription activator with PDZ binding motif) are important in tissue regeneration and cancer development, highlighting the importance of discovering partners that regulate their oncogenicity. SGK1 (serum/glucocorticoid regulated kinase 1), initially identified as a homolog of Akt in phosphoinositide 3-kinase signaling, acts as a serine/threonine protein kinase in multiple oncogenic pathways. However, possible links between SGK1 and Hippo-YAP/TAZ signaling remain unexplored...
August 26, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28608501/targeting-hypoxia-mediated-yap1-nuclear-translocation-ameliorates-pathogenesis-of-endometriosis-without-compromising-maternal-fertility
#12
Shih-Chieh Lin, Hsiu-Chi Lee, Pei-Chi Hou, Jhao-Lin Fu, Meng-Hsing Wu, Shaw-Jenq Tsai
Endometriosis is a highly prevalent gynecological disease that severely reduces women's health and quality of life. Ectopic endometriotic lesions have evolved mechanisms to survive in the hypoxic peritoneal microenvironment by regulating the expression of a significant subset of genes. However, the master regulator controlling these genes remains to be characterized. Herein, by using bioinformatics analysis and experimental verification, we identified Yes-Associated Protein 1 (YAP1) as a master regulator of endometriosis...
June 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28589758/identification-of-type-i-and-type-ii-inhibitors-of-c-yes-kinase-using-in-silico-and-experimental-techniques
#13
Chandrasekaran Ramakrishnan, Anthony Mary Thangakani, Devadasan Velmurugan, Dhanabalan Anantha Krishnan, Masakazu Sekijima, Yutaka Akiyama, M Michael Gromiha
c-Yes kinase is considered as one of the attractive targets for anti-cancer drug design. The DFG (Asp-Phe-Gly) motif present in most of the kinases will adopt active and inactive conformations, known as DFG-in and DFG-out and their inhibitors are classified into type I and type II, respectively. In the present study, two screening protocols were followed for identification of c-Yes kinase inhibitors. (i) Structure-based virtual screening (SBVS) and (ii) Structure-based (SB) and Pharmacophore-based (PB) tandem screening...
June 7, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28575156/consequences-of-endogenous-and-exogenous-wnt-signaling-for-development-of-the-preimplantation-bovine-embryo
#14
Paula Tribulo, Beatriz Caetano da Silva Leão, Khoboso C Lehloenya, Gisele Zoccal Mingoti, Peter J Hansen
The specific role of WNT signaling during preimplantation development remains unclear. Here, we evaluated consequences of activation and inhibition of β-catenin (CTNNB1)-dependent and -independent WNT signaling in the bovine preimplantation embryo. Activation of CTNNB1-mediated WNT signaling by the agonist 2-amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP) and a glycogen synthase kinase 3 inhibitor reduced development to the blastocyst stage. Moreover, the antagonist of WNT signaling, dickkopf-related protein 1 (DKK1), alleviated the negative effect of AMBMP on development via reduction of CTNNB1...
June 1, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28543074/wwc3-regulates-the-wnt-and-hippo-pathways-via-dishevelled-proteins-and-large-tumour-suppressor-1-to-suppress-lung-cancer-invasion-and-metastasis
#15
Qiang Han, Xuyong Lin, Xiupeng Zhang, Guiyang Jiang, Yong Zhang, Yuan Miao, Xuezhu Rong, Xiaoying Zheng, Yong Han, Xu Han, Jingjing Wu, Joachim Kremerskothen, Enhua Wang
The scaffolding protein WWC (WW and C2-domain containing) family is known to regulate cell proliferation and organ size via the Hippo signalling pathway. However, the expression level of WWC3 in human tumours and the mechanisms underlying its role in cellular signal transduction have not yet been reported. Herein, we explored the potential roles of WWC3 in lung cancer cells and the corresponding molecular mechanisms. We found low WWC3 expression in both lung cancer cell lines and lung cancer specimens, which was associated with low differentiation, advanced pTNM stage, positive lymph node metastasis, and poor prognosis in patients with lung cancer...
May 25, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28504812/overexpression-of-the-yap1-oncogene-in-clear-cell-renal-cell-carcinoma-is-associated-with-poor-outcome
#16
Agnieszka Rybarczyk, Jakub Klacz, Agata Wronska, Marcin Matuszewski, Zbigniew Kmiec, Piotr M Wierzbicki
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC (70-80%). Yes-associated protein 1 (YAP1) protein is a nuclear effector of the Hippo pathway and acts as a transcriptional co-activator of genes involved in the processes of growth and development of tissues. Hippo signaling, with its key kinases, MST2 and large tumor suppressor kinase 1 (LATS1), plays a significant role in the negative regulation of the amount and activity of YAP1 protein. Components of the Hippo pathway and YAP1 levels are frequently dysregulated in a variety of tumors, suggestive of their possible involvement in carcinogenesis...
May 15, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28476896/altered-cargo-proteins-of-human-plasma-endothelial-cell-derived-exosomes-in-atherosclerotic-cerebrovascular-disease
#17
Edward J Goetzl, Janice B Schwartz, Maja Mustapic, Iryna V Lobach, Richard Daneman, Erin L Abner, Gregory A Jicha
Plasma endothelial cell-derived exosomes (EDEs) and platelet-derived exosomes (PDEs) were precipitated and enriched separately by immunospecific absorption procedures for analyses of cargo proteins relevant to atherosclerosis. EDEs had usual exosome size and marker protein content, and significantly higher levels than PDEs of the endothelial proteins vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase, whereas PDEs had significantly higher levels of platelet glycoprotein VI. EDE levels of VCAM-1, von Willebrand factor, platelet-derived growth factor (PDGF)-BB, angiopoietin-1, and lysyl oxidase-2 and the cerebrovascular-selective proteins glucose transporter 1, permeability-glycoprotein, and large neutral amino acid transporter 1 were significantly higher for 18 patients with cerebrovascular disease (CeVD) than for 18 age- and gender-matched control subjects...
May 5, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28454447/inhibitory-effect-and-mechanism-of-exogenous-mammalian-sterile-20-like-kinase-1-on-the-growth-of-human-colorectal-cancer
#18
Jian Wu, Xiaohong Yang, Hongfei Lu, Liqiao Liu, Baohua Xu, Shuangyan Zheng, Bo Yu, Kemin Jie, Fusheng Wan
The present study aimed to observe the inhibitory effect and preliminary mechanism of exogenous mammalian sterile 20-like kinase 1 (MST1) on the growth of colorectal cancer SW480 cells. The SW480 cells were randomly divided into the following groups: Control, empty enhanced green fluorescent protein (EGFP) plasmid (pEGFP-N1), MST1 EGFP plasmid (pEGFP-MST1), 20 µmol/l fluorouracil (5-FU) and pEGFP-MST1 + 5-FU. An MTS colorimetric assay was used to detect cell viability, Hoechst 33342 staining was used to observe cell apoptosis, and western blotting and immunohistochemistry were used to detect the levels of the proteins MST1, yes-associated protein (YAP), phospho-YAP1 (Ser127), p53 and p53 upregulated modulator of apoptosis (PUMA)...
April 2017: Oncology Letters
https://www.readbyqxmd.com/read/28428044/transcriptional-co-activator-yap-regulates-camp-signaling-in-sertoli-cells
#19
Souvik Sen Sharma, Subeer S Majumdar
FSH mediated cyclic AMP (cAMP) signaling is crucial for function of testicular Sertoli cells (Sc) during puberty. Yes-kinase Associated Protein (YAP), a transcriptional co-activator, regulates cell proliferation and differentiation. However, its role in testicular function is not known. In present study, we have identified YAP as an important regulator of cAMP signaling in Sc, in-vitro. Verteporfin, a YAP-inhibitor, down regulated the expression of cAMP responsive genes necessary for spermatogenesis in Sc. Action of forskolin, which acts via cAMP, was also antagonized by verteporfin, limiting expression of these genes...
April 18, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28427193/targeting-high-aurora-kinases-expression-as-an-innovative-therapy-for-hepatocellular-carcinoma
#20
Fuchen Liu, Guangyong Wang, Xiaoqiang Wang, Zhihui Che, Wei Dong, Xinggang Guo, Zhenguang Wang, Ping Chen, Daisen Hou, Qi Zhang, Wenli Zhang, Yida Pan, Dongqin Yang, Hui Liu
The Aurora kinases A and B control tumorigenesis by inhibiting apoptosis and promoting proliferation and metastasis, however, it remains unknown whether Aurora A and B overexpressed concomitantly and its clinical significance in hepatocellular carcinoma (HCC). Here, we obsearved Aurora A and B tended to overexpress parallelly on protein level (r = 0.8679, P < 0.0001) and their co-overexpression (Aurora AHBH), associated with the worst prognosis, was an independent predictor for the survival. Importantly, with the lower IC50 and stronger anti-tumor effect than selective inhibitors, SNS-314, the pan-inhibitor of Aurora kinases, which induced YAP (Yes-associated protein) reduction and resulted in P21 accumulation, significantly promoted the polyploidy (> 4N) formation and apoptosis in HCC...
April 25, 2017: Oncotarget
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