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Hanlin Ma, Yingwei Li, Xiangxiang Wang, Huan Wu, Gonghua Qi, Rongrong Li, Ning Yang, Min Gao, Shi Yan, Cunzhong Yuan, Beihua Kong
High-grade serous ovarian carcinoma (HGSOC) is the most lethal type of gynecologic malignancy. Chemoresistance is the main reason for the poor prognosis of HGSOC. PDZ-binding kinase (PBK) promotes the malignant progression of various carcinomas. However, the roles and clinical significance of PBK in HGSOC remain unclear. Here, we reported that PBK was overexpressed in HGSOC tissues and cell lines. High PBK expression was associated with a poor prognosis, metastasis, and cisplatin resistance of HGSOC. Overexpression of PBK promoted autophagy and enhanced cisplatin resistance via the ERK/mTOR signaling pathway...
February 18, 2019: Cell Death & Disease
Xuan Wu, Yunpeng Zhang, Yixiao Xing, Bin Zhao, Cong Zhou, Yong Wen, Xin Xu
BACKGROUND: Type 2 diabetes mellitus (T2DM) and hyperlipidemia are negatively related to bone regeneration. The aim of this study was to evaluate the effect of high-fat and high-glucose microenvironment on bone regeneration and to detect the expression of runt-related transcription factor 2 (Runx2) and transcriptional co-activator with PDZ-binding domain (TAZ) during this process. METHODS: After establishing a high-fat and high-glucose mouse model, a 1 mm × 1...
February 18, 2019: Journal of Orthopaedic Surgery and Research
Seon Woo A An, Eun-Seok Choi, Wooseon Hwang, Heehwa G Son, Jae-Seong Yang, Keunhee Seo, Hyun-Jun Nam, Nhung T H Nguyen, Eun Ji E Kim, Bo Kyoung Suh, Youngran Kim, Shunji Nakano, Youngjae Ryu, Chang Man Ha, Ikue Mori, Sang Ki Park, Joo-Yeon Yoo, Sanguk Kim, Seung-Jae V Lee
PDZ domain-containing proteins (PDZ proteins) act as scaffolds for protein-protein interactions and are crucial for a variety of signal transduction processes. However, the role of PDZ proteins in organismal lifespan and aging remains poorly understood. Here, we demonstrate that KIN-4, a PDZ domain-containing microtubule-associated serine-threonine (MAST) protein kinase, is a key longevity factor acting through binding PTEN phosphatase in Caenorhabditis elegans. Through a targeted genetic screen for PDZ proteins, we find that kin-4 is required for the long lifespan of daf-2/insulin/IGF-1 receptor mutants...
February 17, 2019: Aging Cell
Amin R Mohamed, Klara L Verbyla, Hawlader A Al-Mamun, Sean McWilliam, Bradley Evans, Harry King, Peter Kube, James W Kijas
BACKGROUND: A key developmental transformation in the life of all vertebrates is the transition to sexual maturity, whereby individuals are capable of reproducing for the first time. In the farming of Atlantic salmon, early maturation prior to harvest size has serious negative production impacts. RESULTS: We report genome wide association studies (GWAS) using fish measured for sexual maturation in freshwater or the marine environment. Genotypic data from a custom 50 K single nucleotide polymorphism (SNP) array was used to identify 13 significantly associated SNP for freshwater maturation with the most strongly associated on chromosomes 10 and 11...
February 15, 2019: BMC Genomics
Yongsheng Yu, Shuangdi Li, Kai Wang, Xiaoping Wan
Melanoma differentiation-associated gene 9 (MDA-9)/Syntenin is a multidomain PDZ protein and identified as a key oncogene in melanoma initially. This protein contains a unique tandem PDZ domain architecture (PDZ1 and PDZ2 spaced by a 4-amino acid linker), an N-terminal domain (NTD) that is structurally uncharacterized and a short C-terminal domain (CTD). The PDZ1 domain is regarded as the PDZ signaling domain while PDZ2 served as the PDZ superfamily domain. It has various cellular roles by regulating many of major signaling pathways in numerous cancertypes...
2019: Computational and Structural Biotechnology Journal
Vaishali Kapoor, Abhay Kumar Singh, Buck E Rogers, Dinesh Thotala, Dennis E Hallahan
Targeted molecular imaging allows specific visualization and monitoring of tumors. Cancer-specific peptides have been developed for imaging and therapy. Peptides that specifically target cancer have several advantages including, ease of synthesis, low antigenicity, and enhanced diffusion into tissues. We developed the HVGGSSV peptide as a molecular targeting/imaging agent. HVGGSSV targets Tax interacting protein 1 (TIP1) which is a 14 kDa PDZ domain-containing protein that is overexpressed in cancer. We docked HVGGSSV in silico using the three-dimensional structure of TIP1 and found the binding energy was -6...
February 11, 2019: Journal of Controlled Release: Official Journal of the Controlled Release Society
Mihir V Patel, Emily Sewell, Samantha Dickson, Hyuck Kim, David Meaney, Bonnie L Firestein
Postsynaptic density 95 (PSD-95), the major scaffold protein at excitatory synapses, plays a major role in mediating intracellular signaling by synaptic N-methyl-D-aspartate (NMDA) type glutamate receptors. Despite the fact that much is known about the role of PSD-95 in NMDA-mediated toxicity, less is known about its role in mechanical injury, and more specifically, in traumatic brain injury. Given that neural circuitry is disrupted after TBI and that PSD-95 and its interactors end-binding protein 3 (EB3) and adenomatous polyposis coli (APC) shape dendrites, we examined whether changes to these proteins and their interactions occur after brain trauma...
February 12, 2019: Journal of Neurotrauma
A Rum Kim, Jung Il Park, Ho Taek Oh, Kyung Min Kim, Jun-Ha Hwang, Mi Gyeong Jeong, Ee-Hyun Kim, Eun Sook Hwang, Jeong-Ho Hong
In response to liver injury, the liver undergoes a regeneration process to retain its mass and function. However, the regeneration mechanism has not been fully clarified. This study investigated the role of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo-signaling effector, in liver regeneration. We observed that TAZ stimulates liver regeneration after liver injury. After partial hepatectomy (PHx) or carbon tetrachloride damage, TAZ was required for liver regeneration to increase hepatic cell proliferation and resist hepatic apoptosis, which were decreased in liver-specific TAZ knockout (LKO) mice...
February 11, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Shehla U Hridi, Aimée J P M Franssen, Hui-Rong Jiang, Trevor J Bushell
Interleukin 16 (IL-16) is a cytokine that is primarily associated with CD4+ T cell function, but also exists as a multi-domain PDZ protein expressed within cerebellar and hippocampal neurons. We have previously shown that lymphocyte-derived IL-16 is neuroprotective against excitotoxicity, but evidence of how it affects neuronal function is limited. Here, we have investigated whether IL-16 modulates neuronal excitability and synaptic activity in mouse primary hippocampal cultures. Application of recombinant IL-16 impairs both glutamate-induced increases in intracellular Ca2+ and sEPSC frequency and amplitude in a CD4- and CD9-independent manner...
February 6, 2019: Molecular and Cellular Neurosciences
Markus Horsthemke, Lauryl M J Nutter, Anne C Bachg, Boris V Skryabin, Ulrike Honnert, Thomas Zobel, Sven Bogdan, Monika Stoll, Matthias D Seidl, Frank U Mueller, Ursula Ravens, Andreas Unger, Wolfgang A Linke, Pim R R van Gorp, Antoine A F de Vries, Martin Bähler, Peter J Hanley
Whereas myosin 18B (Myo18B) is known to be a critical sarcomeric protein, the function of myosin 18A (Myo18A) is unclear, although it has been implicated in cell motility and Golgi shape. Here we show that homozygous deletion (homozygous tm1a, tm1b or tm1d alleles) of Myo18a in mouse is embryonic lethal. Reminiscent of Myo18b, Myo18a was highly expressed in the embryo heart, and cardiac-restricted Myo18a deletion in mice was embryonic lethal. Surprisingly, using Western blot analysis, we were unable to detect the known isoforms of Myo18A, Myo18Aα and Myo18Aβ, in mouse heart using a custom C-terminal antibody...
February 8, 2019: Journal of Biological Chemistry
Matthias Van Haele, Iván M Moya, Ruçhan Karaman, Guy Rens, Janne Snoeck, Olivier Govaere, Frederik Nevens, Chris Verslype, Baki Topal, Diethard Monbaliu, Georg Halder, Tania Roskams
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19⁺), hepatocellular carcinoma keratin 19 negative (HCC K19- ), combined hepatocellular⁻cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA)...
February 1, 2019: International Journal of Molecular Sciences
Na Wang, Yukun Li, Ziyi Li, Jianxia Ma, Xuelun Wu, Runzhou Pan, Yan Wang, Liu Gao, Xiaoxue Bao, Peng Xue
Gene modification of mesenchymal stem cells (MSCs) offers a promising approach for clinical stem cell therapy. Transcriptional co-activator with PDZ-binding motif (TAZ) plays a vital role in MSCs' differentiation. We aim to explore the interaction of insulin receptor substrate-1 (IRS-1) with TAZ to regulate MSCs' adipogenesis in this study. Initially, IRS-1 and TAZ followed similar decreasing expression pattern at the early stage of adipogenesis. And, overexpression of IRS-1 decreased the CCAAT/enhancer binding protein β (C/EBPβ) and peroxi-some proliferator-activated receptor gamma (PPARγ) expression with TAZ upregulation...
February 1, 2019: European Journal of Pharmacology
Xu Liu, Ernesto J Fuentes
Post-synaptic density-95, disks-large and zonula occludens-1 (PDZ) domains are small globular protein-protein interaction domains widely conserved from yeast to humans. They are composed of ∼90 amino acids and form a classical two α-helical/six β-strand structure. The prototypical ligand is the C-terminus of partner proteins; however, they also bind internal peptide sequences. Recent findings indicate that PDZ domains also bind phosphatidylinositides and cholesterol. Through their ligand interactions, PDZ domain proteins are critical for cellular trafficking and the surface retention of various ion channels...
2019: International Review of Cell and Molecular Biology
Roohollah Mohseni, Jamshid Karimi, Heidar Tavilani, Iraj Khodadadi, Mohammad Hashemnia
OBJECTIVE: Little is known about the exact underlying molecular mechanisms of the hepatoprotective effect of carvacrol against liver fibrosis. In the current study, we aimed to investigate the effect of carvacrol on the suppression of liver fibrosis progression via regulation of yes-associated protein (YAP) and transcriptional coactivators with a PDZ-binding motif (TAZ) and transforming growth factor beta (TGF-β) pathway. MATERIALS AND METHODS: To fulfill our target, rats received carbon tetrachloride (CCl4 ) and carvacrol intraperitoneally, and orally, respectively for 10 weeks...
February 1, 2019: Immunopharmacology and Immunotoxicology
Vijaykumar Yogesh Muley, Yusuf Akhter, Sanjeev Galande
The PSD-95/Dlg-A/ZO-1 (PDZ) domain is highly expanded, diversified and well distributed across the metazoa where it assembles diverse signalling components by virtue of interactions with other proteins in a sequence-specific manner. In contrast, in the microbial world they are reported to be involved in protein quality control during stress response. The distribution, functions, and origins of PDZ domain-containing proteins in the prokaryotic organisms remain largely unexplored. We analysed 7,852 PDZ domain-containing proteins in 1,474 microbial genomes in this context...
January 29, 2019: Genome Biology and Evolution
Qiangmin Zhang, Kunhong Xiao, José M Paredes, Tatyana Mamonova, W Bruce Sneddon, Hongda Liu, Dawei Wang, Sheng Li, Jennifer C McGarvey, David Uehling, Rima Al-Awar, Babu Joseph, Frederic Jean-Alphonse, Angel Orte, Peter A Friedman
Na+ -H+ exchanger regulatory factor-1 (NHERF1) is a PDZ protein that scaffolds membrane proteins, including Na-phosphate co-transport protein 2A (NPT2A) at the plasma membrane. NHERF1 is a phosphoprotein with 40 Ser and Thr residues. Here, using tandem MS analysis, we characterized the sites of parathyroid hormone (PTH)-induced NHERF1 phosphorylation and identified 10 high-confidence phosphorylation sites. Ala replacement at Ser46 , Ser162 , Ser181 , Ser269 , Ser280 , Ser291 , Thr293 , Ser299 , and Ser302 did not affect phosphate uptake, but Ser290 Ala substitution abolished PTH-dependent phosphate transport...
January 29, 2019: Journal of Biological Chemistry
Leo Th Tang, Carlos A Diaz-Balzac, Maisha Rahman, Nelson J Ramirez-Suarez, Yehuda Salzberg, Maria I Lázaro-Peña, Hannes E Bülow
Dendritic arbors are a crucial for nervous system assembly, but the intracellular mechanisms that govern their assembly remain incompletely understood. Here we show that the dendrites of PVD neurons in Caenorhabditis elegans are patterned by distinct pathways downstream of the DMA-1 leucine rich transmembrane (LRR-TM) receptor. DMA-1/LRR-TM interacts through a PDZ ligand motif with the guanine nucleotide exchange factor TIAM-1/GEF in a complex with act-4/Actin to pattern higher order 4º dendrite branches by localizing F-actin to the distal ends of developing dendrites...
January 29, 2019: ELife
Sébastien Tabariès, Alexander McNulty, Véronique Ouellet, Matthew G Annis, Mireille Dessureault, Maude Vinette, Yasmina Hachem, Brennan Lavoie, Atilla Omeroglu, Hans-Georg Simon, Logan A Walsh, Siker Kimbung, Ingrid Hedenfalk, Peter M Siegel
Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding motif of Claudin-2 in liver metastatic breast cancer cells, including Afadin, Arhgap21, Pdlim2, Pdlim7, Rims2, Scrib, and ZO-1. We specifically examined the role of Afadin as a potential Claudin-2-interacting partner that promotes breast cancer liver metastasis...
January 28, 2019: Genes & Development
Candice Gautier, Louise Laursen, Per Jemth, Stefano Gianni
Ever since Ranganathan and coworkers subjected the covariation of amino acid residues in the postsynaptic density-95/Discs large/Zonula occludens 1 (PDZ) domain family to a statistical correlation analysis, PDZ domains have represented a paradigmatic family to explore single domain protein allostery. Nevertheless, several theoretical and experimental studies in the past two decades have contributed contradicting results with regard to structural localization of the allosteric networks, or even questioned their actual existence in PDZ domains...
August 2, 2018: Protein Engineering, Design & Selection: PEDS
Paula G Slater, Garrett M Cammarata, Connor Monahan, Jackson T Bowers, Oliver Yan, Sangmook Lee, Laura Anne Lowery
The mammalian guanine deaminase (GDA), called cypin, is important for proper neural development, by regulating dendritic arborization through modulation of microtubule (MT) dynamics. Additionally, cypin can promote MT assembly in vitro. However, it has never been tested whether cypin (or other GDA orthologs) binds to MTs or modulates MT dynamics. Here, we address these questions and characterize Xenopus laevis GDA (Gda) for the first time during embryonic development. We find that exogenously-expressed human cypin and Gda both display a cytosolic distribution in primary embryonic cells...
January 25, 2019: Developmental Dynamics: An Official Publication of the American Association of Anatomists
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