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Haibin Tian, Jing-Ying Xu, Yu Tian, Yaqi Cao, Chunpin Lian, Qingjian Ou, Binxin Wu, Caixia Jin, Furong Gao, Juan Wang, Jieping Zhang, Jingfa Zhang, Weiye Li, Lixia Lu, Guo-Tong Xu
The pathological change of retinal pigment epithelial (RPE) cells is one of the main reasons for the development of age-related macular degeneration (AMD). Thus, cultured RPE cells are a proper cell model for studying the etiology of AMD in vitro. However, such cultured RPE cells easily undergo epithelial-mesenchymal transition (EMT) that results in changes of cellular morphology and functions of the cells. To restore and maintain the mesenchymal-epithelial transition (MET) of the cultured RPE cells, we cultivated dedifferentiated porcine RPE (pRPE) cells and compared their behaviors in four conditions: 1) in cell culture dishes with DMEM/F12 containing FBS (CC dish-FBS), 2) in petri dishes with DMEM/F12 containing FBS (Petri dish-FBS), 3) in cell culture dishes with DMEM/F12 containing N2 and B27 supplements (CC dish-N2B27), and 4) in petri dishes with DMEM/F12 containing N2 and B27 (Petri dish-N2B27)...
August 7, 2018: Experimental Eye Research
Jing-Yi Zhu, Sen Lin, Jian Ye
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators established as a nexus in numerous signaling pathways, notably in Hippo signaling. Previous research revealed multifarious function of YAP and TAZ in oncology and cardiovasology. Recently, the focus has been laid on their pivotal role in eye morphogenesis and homeostasis. In this review, we synthesize advances of YAP and TAZ function during eye development in different model organisms, introduce their function in different ocular tissues and eye diseases, and highlight the potential for therapeutic interventions...
August 10, 2018: Journal of Cellular Physiology
Ja Hyun Koo, Kun-Liang Guan
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two homologous transcriptional coactivators that promote cell proliferation, stem cell maintenance, and tissue homeostasis. Under favorable conditions, YAP and TAZ are active to promote cell growth through a transcriptional program mediated by the TEAD family transcription factors. Given the indispensability of cellular energy and metabolites for survival and growth, YAP and TAZ are inhibited when energy level is low...
August 7, 2018: Cell Metabolism
John R Horsley, Jingxian Yu, Kate L Wegener, Christian Hoppmann, Karola Rück-Braun, Andrew D Abell
Neuronal nitric oxide synthase (nNOS) is an enzyme responsible for catalyzing the production of the crucial cellular signalling molecule, nitric oxide (NO), through its interaction with the PDZ domain of α-syntrophin protein. In this study, a novel light-driven photoswitchable peptide-based biosensor, modelled on the nNOS β-finger, is used to detect and control its interaction with α-syntrophin. An azobenzene photoswitch incorporated into the peptide backbone allows reversible switching between a trans photostationary state devoid of secondary structure, and a cis photostationary state possessing a well-defined antiparallel β-strand geometry, as revealed by molecular modelling...
July 29, 2018: Biosensors & Bioelectronics
Maarten M G van den Hoogenhof, Ingeborg van der Made, Nina E de Groot, Amin Damanafshan, Shirley C M van Amersfoorth, Lorena Zentilin, Mauro Giacca, Yigal M Pinto, Esther E Creemers
The RNA-binding protein Rbm24 has recently been identified as a pivotal splicing factor in the developing heart. Loss of Rbm24 in mice disrupts cardiac development by governing a large number of muscle-specific splicing events. Since Rbm24 knockout mice are embryonically lethal, the role of Rbm24 in the adult heart remained unexplored. Here, we used adeno-associated viruses (AAV9) to investigate the effect of increased Rbm24 levels in adult mouse heart. Using high-resolution microarrays, we found 893 differentially expressed genes and 1102 differential splicing events in 714 genes in hearts overexpressing Rbm24...
August 3, 2018: Scientific Reports
Eseoghene Ifie, Mark A Russell, Shalinee Dhayal, Pia Leete, Guido Sebastiani, Laura Nigi, Francesco Dotta, Varpu Marjomäki, Decio L Eizirik, Noel G Morgan, Sarah J Richardson
AIMS/HYPOTHESIS: The Coxsackie and adenovirus receptor (CAR) is a transmembrane cell-adhesion protein that serves as an entry receptor for enteroviruses and may be essential for their ability to infect cells. Since enteroviral infection of beta cells has been implicated as a factor that could contribute to the development of type 1 diabetes, it is often assumed that CAR is displayed on the surface of human beta cells. However, CAR exists as multiple isoforms and it is not known whether all isoforms subserve similar physiological functions...
August 3, 2018: Diabetologia
Khalid Bashir Dar, Aashiq Hussain Bhat, Shajrul Amin, Syed Anjum, Bilal Ahmad Reshi, Mohammad Afzal Zargar, Akbar Masood, Showkat Ahmad Ganie
Protein-protein interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer...
August 2, 2018: Current Cancer Drug Targets
Jianchun Chen, Huaizhou You, Yan Li, You Xu, Qian He, Raymond C Harris
BACKGROUND: Increasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI...
August 2, 2018: Journal of the American Society of Nephrology: JASN
Takeshi Honda, Makoto Inui
PDZRN3 (also known as LNX3) is a member of the PDZ domain-containing RING finger protein family. We previously showed that PDZRN3 is essential for differentiation of myoblasts into myotubes and that depletion of PDZRN3 inhibits such differentiation downstream of the upregulation of myogenin, a basic helix-loop-helix (bHLH) transcription factor required for completion of the differentiation process. However, the mechanism by which PDZRN3 controls this process has remained unclear. Myogenin is rendered active during the late stage of myogenic differentiation by the downregulation of Id2, a negative regulator of bHLH transcription factors...
August 1, 2018: Journal of Cellular Physiology
Ward G Walkup, Michael J Sweredoski, Robert L Graham, Sonja Hess, Mary B Kennedy
SynGAP is a Ras and Rap GTPase-activating protein (GAP) found in high concentration in the postsynaptic density (PSD) fraction from mammalian forebrain where it binds to PDZ domains of PSD-95. Phosphorylation of pure recombinant synGAP by Ca2+ /calmodulin-dependent protein kinase II (CaMKII) shifts the balance of synGAP's GAP activity toward inactivation of Rap1; whereas phosphorylation by cyclin-dependent kinase 5 (CDK5) has the opposite effect, shifting the balance toward inactivation of HRas. These shifts in balance contribute to regulation of the numbers of surface AMPA receptors, which rise during synaptic potentiation (CaMKII) and fall during synaptic scaling (CDK5)...
July 23, 2018: Biochemical and Biophysical Research Communications
Hidenori Ito, Rika Morishita, Koh-Ichi Nagata
Rhotekin is an effector protein for small GTPase Rho. This protein consists of a Rho binding domain (RBD), a pleckstrin homology (PH) domain, two proline-rich regions and a C-terminal PDZ (PSD-95, Discs-large, and ZO-1)-binding motif. We, and other groups, have identified various binding partners for Rhotekin and carried out biochemical and cell biological characterization. However, the physiological functions of Rhotekin, per se, are as of yet largely unknown. In this review, we summarize known features of Rhotekin and its binding partners in neuronal tissues and cancer cells...
July 20, 2018: International Journal of Molecular Sciences
Varsha Singh, Jianbo Yang, Jianyi Yin, Robert Cole, Ming Tse, Diego E Berman, Scott A Small, Gregory Petsko, Mark Donowitz
Cholera toxin (CT) causes severe diarrhea by increasing intracellular cAMP leading to a PKA dependent increase in Cl- secretion through CFTR and decreased Na+ absorption by inhibition of Na+ /H+ exchanger 3 (NHE3). The mechanism(s) by which CT inhibits NHE3 is partially understood, although no drug therapy has successfully been targeted at reversing this inhibition. We now describe that CT phosphorylates an amino acid in the PDZ domain of SNX27, which inhibits SNX27-mediates trafficking of NHE3 from the early endosomes to plasma membrane and contributes to reduced basal NHE3 activity that involves reduced plasma membrane (PM) expression, and reduced endocytic recycling...
July 20, 2018: Journal of Cell Science
Akiko Futakuchi, Toshihiro Inoue, Fan-Yan Wei, Miyuki Inoue-Mochita, Tomokazu Fujimoto, Kazuhito Tomizawa, Hidenobu Tanihara
Purpose: To investigate the roles of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), the major effector molecules of the Hippo pathway, in TGF-β2-mediated conjunctival fibrosis. Methods: Primary human conjunctival fibroblasts were treated with TGF-β2. The expression of YAP/TAZ was examined by Western blot analyses and immunocytochemistry. The expression of fibrotic proteins and genes were evaluated by Western blot analyses and quantitative real-time PCR, respectively...
June 1, 2018: Investigative Ophthalmology & Visual Science
Miao Yu, Xiaomin Ma, Huaiqing Cao, Bin Chong, Luhua Lai, Zhirong Liu
Many proteins exhibit a critical property called allostery, which enables intra-molecular transmission of information between distal sites. Microscopically, allosteric response is closely related to correlated atomic fluctuations. Conventional correlation analysis correlates the atomic fluctuations at two sites by taking the dot product between the fluctuations, which accounts only for the parallel and antiparallel components. Here, we present a singular value decomposition (SVD) method that analyzes the correlation coefficient of fluctuation dynamics with an arbitrary angle between the correlated directions...
July 18, 2018: Proteins
Lesley A Colgan, Mo Hu, Jaime A Misler, Paula Parra-Bueno, Corey M Moran, Michael Leitges, Ryohei Yasuda
The protein kinase C (PKC) enzymes have long been established as critical for synaptic plasticity. However, it is unknown whether Ca2+ -dependent PKC isozymes are activated in dendritic spines during plasticity and, if so, how this synaptic activity is encoded by PKC. Here, using newly developed, isozyme-specific sensors, we demonstrate that classical isozymes are activated to varying degrees and with distinct kinetics. PKCα is activated robustly and rapidly in stimulated spines and is the only isozyme required for structural plasticity...
August 2018: Nature Neuroscience
Zhuangfeng Weng, Yuan Shang, Zeyang Ji, Fei Ye, Lin Lin, Rongguang Zhang, Jinwei Zhu
BACKGROUND: The slit diaphragm is a specialized adhesion junction between opposing podocytes, establishing the final filtration barrier that prevents passage of proteins from the capillary lumen into the urinary space. Nephrin, the key structural and signaling adhesion molecule expressed in the slit diaphragm, contains an evolutionally conserved, atypical PDZ-binding motif (PBM) reported to bind to a variety of proteins in the slit diaphragm. Several mutations in NPHS1 (the gene encoding nephrin) that result in nephrin lacking an intact PBM are associated with glomerular diseases...
July 13, 2018: Journal of the American Society of Nephrology: JASN
Zhize Chen, Jingjing Xu, Yang Wu, Shaoqing Lei, Huimin Liu, Qingtao Meng, Zhongyuan Xia
Emerging evidence has supported that TAZ (transcriptional co-activator with PDZ binding motif), one transcription co-activator in Hippo signaling pathway, plays an oncogenic role in liver carcinogenesis. Targeting TAZ could be a potential therapeutic approach for liver cancer patients. In the current study, we aim to determine whether diosgenin could be an inhibitor of TAZ in liver cancer cells. We found that diosgenin inhibited the expression of TAZ in liver cancer cells. Moreover, we found that diosgenin inhibited cell growth, induced apoptosis, suppressed cell migration and invasion in part via inhibition of TAZ in liver cancer cells...
July 11, 2018: Biochemical and Biophysical Research Communications
Debasree Sarkar, Tanmoy Jana, Sudipto Saha
Protein-peptide interactions form an important subset of the total protein interaction network in the cell and play key roles in signaling and regulatory networks, and in major biological processes like cellular localization, protein degradation, and immune response. In this work, we have described the LMDIPred web server, an online resource for generalized prediction of linear peptide sequences that may bind to three most prevalent and well-studied peptide recognition modules (PRMs)-SH3, WW and PDZ. We have developed support vector machine (SVM)-based prediction models that achieved maximum Matthews Correlation Coefficient (MCC) of 0...
2018: PloS One
John M Lamar, Vijeyaluxmy Motilal Nehru, Guy Weinberg
Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central nervous system-specific transcription activator. The 10% of EHEs that lack the TAZ⁻CAMTA1 fusion instead have a fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3)...
July 10, 2018: Cancers
Jumpei Kida, Kenji Hata, Eriko Nakamura, Hiroko Yagi, Yoshifumi Takahata, Tomohiko Murakami, Yoshinobu Maeda, Riko Nishimura
Canonical Wnt signalling plays an important role in osteoblast differentiation and bone formation. However, the molecular mechanisms by which canonical Wnt signalling exerts its osteoblastogenic effect remain elusive. Here, we investigated the relationship between lymphoid enhancer-binding factor 1 (LEF1) and transcriptional co-activator with PDZ-binding motif (TAZ), both of which are transcriptional regulators that mediate canonical Wnt signalling during osteoblast differentiation. Reporter assay and co-immunoprecipitation experiments revealed functional and physical interaction between LEF1 and TAZ...
July 10, 2018: Scientific Reports
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