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Yes kinase

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
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
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...
2016: Nutrients
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
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
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
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
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
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...
2016: Nature Communications
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
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
Teresa M Seccia, Brasilina Caroccia, Francesca Gioco, Maria Piazza, Valentina Buccella, Diego Guidolin, Eugenia Guerzoni, Barbara Montini, Lucia Petrelli, Elisa Pagnin, Verdiana Ravarotto, Anna S Belloni, Lorenzo A Calò, Gian Paolo Rossi
BACKGROUND: Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelin-1 (ET-1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ET-1. METHODS AND RESULTS: Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin II-dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ET-1 and/or angiotensin II receptor or left untreated (controls)...
July 2016: Journal of the American Heart Association
Andrew M Brunner, Shuli Li, Amir T Fathi, Martha Wadleigh, Vincent T Ho, Kerry Collier, Christine Connolly, Karen K Ballen, Corey S Cutler, Bimalangshu R Dey, Areej El-Jawahri, Sarah Nikiforow, Steven L McAfee, John Koreth, Daniel J Deangelo, Edwin P Alyea, Joseph H Antin, Thomas R Spitzer, Richard M Stone, Robert J Soiffer, Yi-Bin Chen
We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post-HCT initiation of sorafenib (yes/no) was evaluated as a time-varying covariate in the overall survival/progression-free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation...
July 19, 2016: British Journal of Haematology
Fahim Ahmad, Deobrat Dixit, Shanker Datt Joshi, Ellora Sen
Epigenetic regulation by histone methyltransferase G9a is known to control autophagic responses. As the link between autophagy and metabolic homeostasis is widely accepted, we investigated whether G9a affects metabolic circuitries to affect autophagic response in glioma cells. Both pharmacological inhibition and siRNA mediated knockdown of G9a increased autophagy marker LC3B in glioma cells. G9a inhibitor BIX-01294 (BIX) induced Akt-dependent increase in HIF-1α expression and activity. Inhibition of Akt-HIF-1α axis reversed BIX-mediated (i) increase in LC3B expression and (ii) decrease in Yes-associated protein 1 (YAP1) phosphorylation...
September 2016: International Journal of Biochemistry & Cell Biology
Annika Karch, Armin Koch, Viktor Grünwald
BACKGROUND: Anthracycline-based treatment remains the backbone of chemotherapy for nonresectable soft tissue sarcomas (STS). More than 30 % of patients with STS are aged 60 years or older, limiting the choice of treatment to single-agent approaches for this elderly population. Hematological toxicity is frequent during doxorubicin monotherapy, grade 4 neutropenia is reported in 34 %, with a febrile neutropenia rate of 9 % in STS. We assume that comorbidities in the elderly population may limit tolerability of doxorubicin, and novel agents may improve tolerability and health-related quality of life while maintaining efficacy...
2016: Trials
Jia Wang, James Sinnett-Smith, Jan V Stevens, Steven H Young, Enrique Rozengurt
We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser(127) and Ser(397) Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0...
August 19, 2016: Journal of Biological Chemistry
Anette M Høye, John R Couchman, Ulla M Wewer, Atsuko Yoneda
Integrins, a family of heterodimeric adhesion receptors are implicated in cell migration, development and cancer progression. They can adopt conformations that reflect their activation states and thereby impact adhesion strength and migration. Integrins in an intermediate activation state may be optimal for migration and we have shown previously that fully activated integrin α9β1 corresponds with less migratory behaviour in melanoma cells. Here, we aimed to identify components associated with the activation status of α9β1...
2016: Scientific Reports
Takanori Chiba, Erika Ishihara, Norio Miyamura, Rika Narumi, Mihoko Kajita, Yasuyuki Fujita, Akira Suzuki, Yoshihiro Ogawa, Hiroshi Nishina
Cell competition is a cell-cell interaction by which a cell compares its fitness to that of neighboring cells. The cell with the relatively lower fitness level is the "loser" and actively eliminated, while the cell with the relatively higher fitness level is the "winner" and survives. Recent studies have shown that cells with high Yes-associated protein (YAP) activity win cell competitions but the mechanism is unknown. Here, we report the unexpected finding that cells overexpressing constitutively active YAP undergo apical extrusion and are losers, rather than winners, in competitions with normal mammalian epithelial cells...
2016: Scientific Reports
Dominic P Del Re
Initially identified inDrosophila melanogaster, the Hippo signaling pathway regulates organ size through modulation of cell proliferation, survival and differentiation. This pathway is evolutionarily conserved and canonical signaling involves a kinase cascade that phosphorylates and inhibits the downstream effector Yes-associated protein (YAP). Recent research has demonstrated a fundamental role of Hippo signaling in cardiac development, homeostasis, injury and regeneration, and remains the subject of intense investigation...
June 24, 2016: Circulation Journal: Official Journal of the Japanese Circulation Society
Suowen Xu, Marina Koroleva, Meimei Yin, Zheng Gen Jin
Atherosclerosis is a mechanobiology-related disease that preferentially develops in the aortic arch and arterial branches, which are exposed to disturbed/turbulent blood flow but less in thoracic aorta where the flow pattern is steady laminar flow (LF). Increasing evidence supports that steady LF with high shear stress is protective against atherosclerosis. However, the molecular mechanisms of LF-mediated atheroprotection remain incompletely understood. Hippo/YAP (yes-associated protein) pathway senses and effects mechanical cues and has been reported to be a master regulator of cell proliferation, differentiation, and tissue homeostasis...
October 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
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