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https://www.readbyqxmd.com/read/28065575/multiparametric-analysis-of-cell-shape-demonstrates-that-%C3%AE-pix-directly-couples-yap-activation-to-extracellular-matrix-adhesion
#1
Julia E Sero, Chris Bakal
Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control the activity of mechanosensitive proteins poses a technical challenge, because perturbations that affect cell shape may also affect protein localization indirectly. Here, we present an approach that mitigates confounding effects of cell-shape changes, allowing us to identify direct regulators of YAP localization...
January 2, 2017: Cell Systems
https://www.readbyqxmd.com/read/28049763/the-receptor-tyrosine-kinase-axl-mediates-nuclear-translocation-of-the-epidermal-growth-factor-receptor
#2
Toni M Brand, Mari Iida, Kelsey L Corrigan, Cara M Braverman, John P Coan, Bailey G Flanigan, Andrew P Stein, Ravi Salgia, Jana Rolff, Randall J Kimple, Deric L Wheeler
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance...
January 3, 2017: Science Signaling
https://www.readbyqxmd.com/read/28028053/mrtf-potentiates-tead-yap-transcriptional-activity-causing-metastasis
#3
Tackhoon Kim, Daehee Hwang, Dahye Lee, Jeong-Hwan Kim, Seon-Young Kim, Dae-Sik Lim
Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF) play similar roles and exhibit significant crosstalk in directing transcriptional responses to chemical and physical extracellular cues. The mechanism underlying this crosstalk, however, remains unclear. Here, we show MRTF family proteins bind YAP via a conserved PPXY motif that interacts with the YAP WW domain. This interaction allows MRTF to recruit NcoA3 to the TEAD-YAP transcriptional complex and potentiate its transcriptional activity...
December 27, 2016: EMBO Journal
https://www.readbyqxmd.com/read/28003126/emerging-role-of-hippo-signalling-in-pancreatic-biology-yap-re-expression-and-plausible-link-to-islet-cell-apoptosis-and-replication
#4
REVIEW
Anjana Sharma, Veera Ganesh Yerra, Ashutosh Kumar
Diabetes mellitus is an ailment that develops when the functional capacity of the pancreas does not meet the metabolic requirements of the whole body, either due to insulin insufficiency or resistance to insulin action. Current therapies that control glycaemia are limited by their unwanted effects or their inability to prevent the development of long-term complications. Regeneration and replacement of beta cell therapies are shaping the goals of future management of diabetes. The Hippo pathway, first discovered in Drosophila melanogaster, plays a vital role in controlling the organ size...
December 18, 2016: Biochimie
https://www.readbyqxmd.com/read/28003097/hippo-signaling-in-the-liver-regulates-organ-size-cell-fate-and%C3%A2-carcinogenesis
#5
REVIEW
Sachin Patel, Fernando D Camargo, Dean Yimlamai
The Hippo signaling pathway, also known as the Salvador-Warts-Hippo pathway, is a regulator of organ size. The pathway takes its name from the Drosophila protein kinase, Hippo (STK4/MST1 and STK3/MST2 in mammals), which, when inactivated, leads to considerable tissue overgrowth. In mammals, MST1 and MST2 negatively regulate the transcriptional co-activators yes-associated protein 1 and WW domain containing transcription regulator 1 (WWTR1/TAZ), which together regulate expression of genes that control proliferation, survival, and differentiation...
December 19, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27979972/phosphorylation-by-nlk-inhibits-yap-14-3-3-interactions-and-induces-its-nuclear-localization
#6
Sungho Moon, Wantae Kim, Soyoung Kim, Youngeun Kim, Yonghee Song, Oleksii Bilousov, Jiyoung Kim, Taebok Lee, Boksik Cha, Minseong Kim, Hanjun Kim, Vladimir L Katanaev, Eek-Hoon Jho
Hippo signaling controls organ size by regulating cell proliferation and apoptosis. Yes-associated protein (YAP) is a key downstream effector of Hippo signaling, and LATS-mediated phosphorylation of YAP at Ser127 inhibits its nuclear localization and transcriptional activity. Here, we report that Nemo-like kinase (NLK) phosphorylates YAP at Ser128 both in vitro and in vivo, which blocks interaction with 14-3-3 and enhances its nuclear localization. Depletion of NLK increases YAP phosphorylation at Ser127 and reduces YAP-mediated reporter activity...
January 2017: EMBO Reports
https://www.readbyqxmd.com/read/27901498/targeting-the-vegf-c-vegfr3-axis-suppresses-slug-mediated-cancer-metastasis-and-stemness-via-inhibition-of-kras-yap1-signaling
#7
REVIEW
Yu-Wen Yeh, Ching-Chia Cheng, Shu-Ting Yang, Chi-Feng Tseng, Ting-Yu Chang, Sin-Ying Tsai, Earl Fu, Chien-Ping Chiang, Li-Chuan Liao, Pei-Wen Tsai, Yung-Luen Yu, Jen-Liang Su
Vascular endothelial growth factor-C (VEGF-C) has been implicated in epithelial-mesenchymal transition (EMT) processes and various human cancers, including skin cancer. Skin cancer is an aggressive human malignancy with increasing incidence worldwide; however, the underlying mechanisms involved in VEGF-C-induced skin cancer stemness and metastasis remain unclear. Here, we report that VEGF-C enhances skin cancer migration, invasion and stemness through Slug up-regulation. Oncomine database analysis indicated that the KRAS/MAPK (mitogen-activated protein kinases) pathway and YAP1 (yes-associated protein 1) expression are positively correlated with metastatic skin cancer...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27869648/hippo-signaling-interactions-with-wnt-%C3%AE-catenin-and-notch-signaling-repress-liver-tumorigenesis
#8
Wantae Kim, Sanjoy Kumar Khan, Jelena Gvozdenovic-Jeremic, Youngeun Kim, Jason Dahlman, Hanjun Kim, Ogyi Park, Tohru Ishitani, Eek-Hoon Jho, Bin Gao, Yingzi Yang
Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/β-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC)...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27835600/yap1-enhances-cell-proliferation-migration-and-invasion-of-gastric-cancer-in-vitro-and-in-vivo
#9
Dan Sun, Xiaoting Li, Yingjian He, Wenhui Li, Ying Wang, Huan Wang, Shanshan Jiang, Yan Xin
Yes-associated protein 1 (YAP1) plays an important role in the development of carcinomas such as breast, colorectal, and gastric (GC) cancers, but the role of YAP1 in GC has not been investigated comprehensively. The present study strongly suggests that YAP1 and P62 were significantly up-regulated in GC specimens, compared with normal gastric mucosa. In addition, the YAP1high P62high expression was independently associated with poor prognosis in GC (hazard ratio: 1.334, 95% confidence interval: 1.045-1.704, P = 0...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765911/integrin-%C3%AE-2%C3%AE-1-inhibits-mst1-kinase-phosphorylation-and-activates-yes-associated-protein-oncogenic-signaling-in-hepatocellular-carcinoma
#10
Kwong-Fai Wong, Angela M Liu, Wanjin Hong, Zhi Xu, John M Luk
The Hippo pathway regulates the down-stream target Yes-associated protein (YAP) to maintain organ homeostasis, which is commonly inactivated in many types of cancers. However, how cell adhesion dysregulates the Hippo pathway activating YAP oncogene in hepatocellular carcinoma (HCC) remains unclear. Our findings demonstrate that α2β1 integrin (but not other β1 integrins) expressed in HCC cells, after binding to collagen extracellular matrix, could inhibit MST1 kinase phosphorylation and activate YAP pro-oncogenic activities...
October 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27756880/lyn-expression-predicts-the-response-to-dasatinib-in-a-subpopulation-of-lung-adenocarcinoma-patients
#11
Yu Jin Kim, Sungyoul Hong, Minjung Sung, Min Jeong Park, Kyungsoo Jung, Ka-Won Noh, Doo-Yi Oh, Mi-Sook Lee, Ensel Oh, Young Kee Shin, Yoon-La Choi
Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC)...
October 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27669292/yap-inhibition-by-resveratrol-via-activation-of-ampk-enhances-the-sensitivity-of-pancreatic-cancer-cells-to-gemcitabine
#12
Zhengdong Jiang, Xin Chen, Ke Chen, Liankang Sun, Luping Gao, Cancan Zhou, Meng Lei, Wanxing Duan, Zheng Wang, Qingyong Ma, Jiguang Ma
Resveratrol, a natural polyphenol present in most plants, inhibits the growth of numerous cancers both in vitro and in vivo. Aberrant expression of YAP has been reported to activate multiple growth-regulatory pathways and confer anti-apoptotic abilities to many cancer cells. However, the role of resveratrol in YES-activated protein (YAP) expression and that of YAP in pancreatic cancer cells' response to gemcitabine resistance remain elusive. In this study, we found that resveratrol suppressed the proliferation and cloning ability and induced the apoptosis of pancreatic cancer cells...
September 23, 2016: Nutrients
https://www.readbyqxmd.com/read/27593935/aurora-a-kinase-activates-yap-signaling-in-triple-negative-breast-cancer
#13
S-S Chang, H Yamaguchi, W Xia, S-O Lim, Y Khotskaya, Y Wu, W-C Chang, Q Liu, M-C Hung
The Yes-associated protein (YAP) is an effector that transduces the output of the Hippo pathway to transcriptional modulation. Considering the role of YAP in cancers, this protein has emerged as a key node in malignancy development. In this study, we determined that Aurora A kinase acts as a positive regulator for YAP-mediated transcriptional machinery. Specifically, YAP associates with Aurora A predominantly in the nucleus. Activation of Aurora A can impinge on YAP activity through direct phosphorylation. Moreover, aberrant expression of YAP and Aurora A signaling is highly correlated with triple-negative breast cancer (TNBC)...
September 5, 2016: Oncogene
https://www.readbyqxmd.com/read/27582059/targeting-bcl-2-and-abl-lyn-in-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#14
Jessica T Leonard, Joelle S J Rowley, Christopher A Eide, Elie Traer, Brandon Hayes-Lattin, Marc Loriaux, Stephen E Spurgeon, Brian J Druker, Jeffrey W Tyner, Bill H Chang
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies...
August 31, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27571702/ameliorative-effects-of-artemisia-argyi-folium-extract-on-2-4%C3%A2-dinitrochlorobenzene%C3%A2-induced-atopic-dermatitis%C3%A2-like-lesions-in-balb-c-mice
#15
Hyoung-Min Han, Seung-Ju Kim, Jong-Sik Kim, Bum Hoi Kim, Hai Woong Lee, Yong Tae Lee, Kyung-Hwa Kang
Artemisia argyi Folium has been used to treat skin diseases, including eczema and dermatitis, in South Korean medicine. The present study investigated the curative effects of Artemisia argyi Folium extract (AAFE) on 2,4‑dinitrochlorobenzene (DNCB)‑induced atopic dermatitis (AD)‑like skin lesions in a BALB/c mouse model. Briefly, the dorsal skin of the BALB/c mice was sensitized three times with DNCB, whereas the ears were challenged twice. Repeated treatment with DNCB induced AD‑like lesions. The effects of AAFE on AD‑like lesions were evaluated by clinical observation, histopathological analysis, immunohistochemistry and enzyme‑linked immunosorbent assay...
October 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27550814/role-of-src-family-kinases-in-regulation-of-intestinal-epithelial-homeostasis
#16
Shinya Imada, Yoji Murata, Takenori Kotani, Masaki Hatano, Chunxiao Sun, Tasuku Konno, Jung-Ha Park, Yasuaki Kitamura, Yasuyuki Saito, Hideki Ohdan, Takashi Matozaki
Proper regulation of epithelial cell turnover is important for the structural integrity and homeostasis of various tissues including the intestine. Here we show that ablation of Csk, a negative regulator of Src family kinases (SFKs), specifically in intestinal epithelial cells (IECs) resulted in the development of hyperplasia throughout the intestinal epithelium of mice. Such conditional ablation of Csk also increased the proliferative activity and turnover of IECs, disturbed the differentiation of Paneth and goblet cells, reduced the number of intestinal stem cells, and attenuated the expression of Wnt target genes in the intestine...
August 22, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27535619/pharmacological-targeting-of-kinases-mst1-and-mst2-augments-tissue-repair-and-regeneration
#17
Fuqin Fan, Zhixiang He, Lu-Lu Kong, Qinghua Chen, Quan Yuan, Shihao Zhang, Jinjin Ye, Hao Liu, Xiufeng Sun, Jing Geng, Lunzhi Yuan, Lixin Hong, Chen Xiao, Weiji Zhang, Xihuan Sun, Yunzhan Li, Ping Wang, Lihong Huang, Xinrui Wu, Zhiliang Ji, Qiao Wu, Ning-Shao Xia, Nathanael S Gray, Lanfen Chen, Cai-Hong Yun, Xianming Deng, Dawang Zhou
Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration...
August 17, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27535340/pak-proteins-and-yap-1-signalling-downstream-of-integrin-beta-1-in-myofibroblasts-promote-liver-fibrosis
#18
Katherine Martin, James Pritchett, Jessica Llewellyn, Aoibheann F Mullan, Varinder S Athwal, Ross Dobie, Emma Harvey, Leo Zeef, Stuart Farrow, Charles Streuli, Neil C Henderson, Scott L Friedman, Neil A Hanley, Karen Piper Hanley
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts...
August 18, 2016: Nature Communications
https://www.readbyqxmd.com/read/27461598/a-review-on-oral-cancer-biomarkers-understanding-the-past-and-learning-from-the-present
#19
REVIEW
Arvind Babu Rajendra Santosh, Thaon Jones, John Harvey
Biomarkers are broadly classified as genomic, proteomic, or metabolomic. Molecular biology and oncology research studies on oral cancer biomarkers focus on identifying key biological molecules or markers that could be linked to cancer development, risk assessment, screening, recurrence prediction, indicating prognosis, indicating invasion/metastasis and monitoring therapeutic responses of cancer. Cluster of differentiation factor 34 is a salivary biomarker that can identify recurrence potential of oral squamous cell carcinoma (OSCC)...
April 2016: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/27457684/identification-and-characterization-of-the-role-of-c-terminal-src-kinase-in-dengue-virus-replication
#20
Rinki Kumar, Tanvi Agrawal, Naseem Ahmed Khan, Yuji Nakayama, Guruprasad R Medigeshi
We screened a siRNA library targeting human tyrosine kinases in Huh-7 cells and identified c-terminal Src kinase (Csk) as one of the kinases involved in dengue virus replication. Knock-down of Csk expression by siRNAs or inhibition of Csk by an inhibitor reduced dengue virus RNA levels but did not affect viral entry. Csk partially colocalized with viral replication compartments. Dengue infection was drastically reduced in cells lacking the three ubiquitous src family kinases, Src, Fyn and Yes. Csk knock-down in these cells failed to block dengue virus replication suggesting that the effect of Csk is via regulation of Src family kinases...
2016: Scientific Reports
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