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Yoko Shigeno-Nakazawa, Takuma Kasai, Sewon Ki, Elina Kostyanovskaya, Jana Pawlak, Junya Yamagishi, Noriaki Okimoto, Makoto Taiji, Mariko Okada, Jody Westbrook, Yoko Satta, Takanori Kigawa, Akira Imamoto
CRK and CRKL adapter proteins play essential roles in development and cancer through their SRC homology 2 and 3 (SH2 and SH3) domains. To gain insight into the origin of their shared functions, we have investigated their evolutionary history. We propose a term, crk/crkl ancestral (crka), for orthologs in invertebrates before the divergence of CRK and CRKL in the vertebrate ancestor. We have isolated two orthologs expressed in the choanoflagellate Monosiga brevicollis, a unicellular relative to the metazoans...
September 30, 2016: Scientific Reports
Magdalena Koczkowska, Jolanta Wierzba, Robert Śmigiel, Maria Sąsiadek, Magdalena Cabała, Ryszard Ślężak, Mariola Iliszko, Iwona Kardaś, Janusz Limon, Beata S Lipska-Ziętkiewicz
Chromosome 22q11.2 deletion syndrome, one of the most common human genomic syndromes, has highly heterogeneous clinical presentation. Patients usually harbor a 1.5 to 3 Mb hemizygous deletion at chromosome 22q11.2, resulting in pathognomic TBX1, CRKL and/or MAPK1 haploinsufficiency. However, there are some individuals with clinical features resembling the syndrome who are eventually diagnosed with genomic disorders affecting other chromosomal regions. The objective of this study was to evaluate the additive value of high-resolution array-CGH testing in the cohort of 41 patients with clinical features of 22q11...
September 14, 2016: Journal of Applied Genetics
Peter M Benz, Hebatullah Laban, Joana Zink, Lea Günther, Ulrich Walter, Stepan Gambaryan, Karim Dib
BACKGROUND: Vasodilator-Stimulated Phosphoprotein (VASP) is involved in the inhibition of agonist-induced platelet aggregation by cyclic nucleotides and the adhesion of platelets to the vascular wall. αIIbβ3 is the main integrin responsible for platelet activation and Rap1b plays a key role in integrin signalling. We investigated whether VASP is involved in the regulation of Rap1b in platelets since VASP-null platelets exhibit augmented adhesion to endothelial cells in vivo. METHODS: Washed platelets from wild type and VASP-deficient mice were stimulated with thrombin, the purinergic receptors agonist ADP, or the thromboxane A2 receptor agonist U46619 and Rap1b activation was measured using the GST-RalGDS-RBD binding assay...
2016: Cell Communication and Signaling: CCS
Satona Tanaka, Toyofumi F Chen-Yoshikawa, Moto Kajiwara, Toshi Menju, Keiji Ohata, Mamoru Takahashi, Takeshi Kondo, Kyoko Hijiya, Hideki Motoyama, Akihiro Aoyama, Satohiro Masuda, Hiroshi Date
BACKGROUND: Ischemia/reperfusion injury (IRI) remains a significant complication after lung transplantation. Endothelial damage and inflammation contribute to its development. Imatinib has been reported to regulate vascular permeability by maintaining endothelial junctions and showing antiinflammatory effects through inhibition of the Abl kinases. We hypothesized that imatinib could have a protective effect against IRI. METHODS: Male Lewis rats were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes followed by reperfusion for 120 minutes...
July 23, 2016: Annals of Thoracic Surgery
Yan Wang, Xue Dong, Bin Hu, Xiao-Jing Wang, Qian Wang, Wu-Liang Wang
MicroRNA-429 (miR-429) has been suggested to inhibit epithelial-mesenchymal transition (EMT), mainly due to targeting of ZEB1 and ZEB2, which are repressors of the cell to cell contact protein, E-cadherin. In this study, we indicated that regulation of miR-429 in cervical cancer cells modulates cell migration, elongation, as well as transforming growth factor β (TGF-β)-induced stress fiber formation through regulating the cytoskeleton reorganization which is likely independent of the zinc finger E-box binding homeobox (ZEB)/E-cadherin axis...
May 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Leena Ylösmäki, Riku Fagerlund, Inka Kuisma, Ilkka Julkunen, Kalle Saksela
The non-structural protein-1 (NS1) of many influenza A strains, especially those of avian origin, contains an SH3 ligand motif, which binds tightly to the cellular adaptor proteins Crk (Chicken tumor virus number 10 (CT10) regulator of kinase) and Crk-like adapter protein (CrkL). This interaction has been shown to potentiate NS1-induced activation of the phosphatidylinositol 3-kinase (PI3K), but additional effects on the host cell physiology may exist. Here we show that NS1 can induce an efficient translocation of Crk proteins from the cytoplasm into the nucleus, which results in an altered pattern of nuclear protein tyrosine phosphorylation...
April 2016: Viruses
Rong An, Yisong Wang, Donna Voeller, Arjan Gower, In-Kyu Kim, Yu-Wen Zhang, Giuseppe Giaccone
Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in a small subset of patients with non-small-cell lung cancer (NSCLC). The ALK inhibitors are highly effective in NSCLC patients harboring ALK rearrangements; however, most patients acquire resistance to the therapy following an initial response. Mechanisms of acquired resistance are complex. We used LC-MS/MS-based phosphotyrosine-peptide profiling in the EML4-ALK rearranged H3122 and H2228 cells treated with ALK inhibitors, to identify downstream effectors of ALK...
May 17, 2016: Oncotarget
Amaya Bengoa-Alonso, Mercè Artigas-López, María Moreno-Igoa, Claudio Cattalli, Blanca Hernández-Charro, Maria Antonia Ramos-Arroyo
The 22q11.2 deletion syndrome is typically caused by haploinsufficiency of a 3 Mb region that extends from LCR22-A until LCR22-D, while the recurrent recombination between any of the LCR22-D to H causes the 22q11.2 distal deletion syndrome. Here, we describe three patients with a de novo atypical ∼1.4 Mb 22q11.2 deletion that involves LCR22-C to a region beyond D (LCR22-C to D/E), encompassing the distal portion of the typical deleted region and the proximal portion of the distal deletion. We also review six previous published patients with the same rearrangement and compare their features with those found in patients with overlapping deletions...
June 2016: American Journal of Medical Genetics. Part A
Fangzheng Wang, Chuner Jiang, Quanquan Sun, Fenqin Yan, Lei Wang, Zhenfu Fu, Tongxin Liu, Fujun Hu
Viral, dietary and genetic factors have been implicated in nasopharyngeal carcinoma (NPC), however, the molecular mechanism underlying its pathogenesis remains to be fully elucidated. MicroRNAs (miRNAs) have been reported to be important in NPC tumorigenesis, with a previous miRNA microarray study showing the downregulation of miRNA (miR)‑429 in NPC cells. However, the possible mechanisms of action of miR‑429 have not been examined. In the present study, the expression profiles of miR‑429 were detected using reverse transcription‑quantitative polymerase chain reaction analysis in CNE‑1 and CNE‑2 cells, which are two generally used NPC cells with different degrees of differentiation...
April 2016: Molecular Medicine Reports
Christoph Schweingruber, Paolo Soffientini, Marc-David Ruepp, Angela Bachi, Oliver Mühlemann
Proximity-dependent trans-biotinylation by the Escherichia coli biotin ligase BirA mutant R118G (BirA*) allows stringent streptavidin affinity purification of proximal proteins. This so-called BioID method provides an alternative to the widely used co-immunoprecipitation (co-IP) to identify protein-protein interactions. Here, we used BioID, on its own and combined with co-IP, to identify proteins involved in nonsense-mediated mRNA decay (NMD), a post-transcriptional mRNA turnover pathway that targets mRNAs that fail to terminate translation properly...
2016: PloS One
Ye Cao, Zhihua Li, Jill A Rosenfeld, Amber N Pursley, Ankita Patel, Jin Huang, Huilin Wang, Min Chen, Xiaofang Sun, Tak Yeung Leung, Sau Wai Cheung, Kwong Wai Choy
PURPOSE: We sought to investigate the utility of chromosomal microarray analysis (CMA) for prenatal diagnosis of oral clefts, as compared with traditional chromosome analysis, for improved prenatal genetic counseling and discovery of a potential correlation between genotype and oral cleft. METHODS: This retrospective analysis encompassed 270 prenatal oral cleft cases with documented detailed ultrasound findings and CMA results from four referral centers. Detection rates for pathogenic copy-number variants (CNVs) were calculated and compared with cases for which chromosome analysis was also performed...
October 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Ying-Hua Li, Xue-Dong Liu, Xiu-Fen Guo, Xiao Liu, Jian-Min Luo, Zhi-Shang Li, Yong-Xiao Zhang
OBJECTIVE: To explore the effect of overexpression of SH2-containing tyrosine phosphatase 1 (SHP-1) on sensitivity of chronic myelogenous 1eukemia (CML) K562 cell line to imatinib and its related mechamism. METHODS: K562 cells were infected with the lentiviral plasmids containing the specified retroviral vector (pEX-SHP-1-puro-Lv105) or the mock vector (pEX-EGFP-puro-Lv105). The expression of SHP-1 in K562 cells treated with 0.2 µmol/L imatinib (IM) for 72 h was determined by Western blot...
February 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Mauro Giacomelli, Rajesh Kumar, Annarosa Soresina, Nicola Tamassia, Tiziana Lorenzini, Daniele Moratto, Sara Gasperini, Marco Cassatella, Alessandro Plebani, Vassilios Lougaris, Raffaele Badolato
BACKGROUND: Partial DiGeorge syndrome (pDGS) is caused by deletion of the 22q11.2 region. Within this region lies CrK-like (CRKL), a gene encoding an adapter protein belonging to the Crk family that is involved in the signaling cascade of IL-2, stromal cell-derived factor 1α, and type I interferon. Although recurrent infections can be observed in patients with deletion of chromosome 22 syndrome, the immune pathogenesis of this condition is yet not fully understood. OBJECTIVE: We aimed to investigate the role of CRKL in T-cell functional responses in patients affected with pDGS...
July 2016: Journal of Allergy and Clinical Immunology
Xiaofei Liang, Xiaochuan Liu, Beilei Wang, Fengming Zou, Aoli Wang, Shuang Qi, Cheng Chen, Zheng Zhao, Wenchao Wang, Ziping Qi, Fengchao Lv, Zhenquan Hu, Li Wang, Shanchun Zhang, Qingsong Liu, Jing Liu
Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM)...
March 10, 2016: Journal of Medicinal Chemistry
Tom Ronan, Jennifer L Macdonald-Obermann, Lorel Huelsmann, Nicholas J Bessman, Kristen M Naegle, Linda J Pike
The EGF receptor can bind seven different agonist ligands. Although each agonist appears to stimulate the same suite of downstream signaling proteins, different agonists are capable of inducing distinct responses in the same cell. To determine the basis for these differences, we used luciferase fragment complementation imaging to monitor the recruitment of Cbl, CrkL, Gab1, Grb2, PI3K, p52 Shc, p66 Shc, and Shp2 to the EGF receptor when stimulated by the seven EGF receptor ligands. Recruitment of all eight proteins was rapid, dose-dependent, and inhibited by erlotinib and lapatinib, although to differing extents...
March 11, 2016: Journal of Biological Chemistry
Leo Y Luo, William C Hahn
Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2...
October 20, 2015: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Peter T Hallock, Sherry Chin, Steven Blais, Thomas A Neubert, David J Glass
Crk and CrkL are noncatalytic adaptor proteins necessary for the formation of neuromuscular synapses which function downstream of muscle-specific kinase (MuSK), a receptor tyrosine kinase expressed in skeletal muscle, and the MuSK binding protein Dok-7. How Crk/CrkL regulate neuromuscular endplate formation is not known. To better understand the roles of Crk/CrkL, we identified CrkL binding proteins using mass spectrometry and have identified Sorbs1 and Sorbs2 as two functionally redundant proteins that associate with the initiating MuSK/Dok-7/Crk/CrkL complex, regulate acetylcholine receptor (AChR) clustering in vitro, and are localized at synapses in vivo...
November 2, 2015: Molecular and Cellular Biology
Yoji Ishida, Kazunori Murai, Kohei Yamaguchi, Takuto Miyagishima, Motohiro Shindo, Kazuei Ogawa, Takahiro Nagashima, Shinji Sato, Reiko Watanabe, Satoshi Yamamoto, Takayuki Hirose, Souich Saitou, Masakatsu Yonezumi, Takeshi Kondo, Yuichi Kato, Noboru Mochizuki, Keiko Ohno, Satoshi Kishino, Kohmei Kubo, Tatsuo Oyake, Shigeki Ito
PURPOSE: Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients. METHODS: The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)CD34+cells) was calculated from each patient's dose-response curve using flow cytometry...
February 2016: European Journal of Clinical Pharmacology
Rajmohan Murali, Raghu Chandramohan, Inga Möller, Simone L Scholz, Michael Berger, Kety Huberman, Agnes Viale, Mono Pirun, Nicholas D Socci, Nancy Bouvier, Sebastian Bauer, Monika Artl, Bastian Schilling, Tobias Schimming, Antje Sucker, Benjamin Schwindenhammer, Florian Grabellus, Michael R Speicher, Jörg Schaller, Uwe Hillen, Dirk Schadendorf, Thomas Mentzel, Donavan T Cheng, Thomas Wiesner, Klaus G Griewank
Angiosarcomas are rare malignant mesenchymal tumors of endothelial differentiation. The clinical behavior is usually aggressive and the prognosis for patients with advanced disease is poor with no effective therapies. The genetic bases of these tumors have been partially revealed in recent studies reporting genetic alterations such as amplifications of MYC (primarily in radiation-associated angiosarcomas), inactivating mutations in PTPRB and R707Q hotspot mutations of PLCG1. Here, we performed a comprehensive genomic analysis of 34 angiosarcomas using a clinically-approved, hybridization-based targeted next-generation sequencing assay for 341 well-established oncogenes and tumor suppressor genes...
November 3, 2015: Oncotarget
Daniel Garcia de la Serrana, Robert H Devlin, Ian A Johnston
BACKGROUND: Coho salmon (Oncorhynchus kisutch) transgenic for growth hormone (Gh) express Gh in multiple tissues which results in increased appetite and continuous high growth with satiation feeding. Restricting Gh-transgenics to the same lower ration (TR) as wild-type fish (WT) results in similar growth, but with the recruitment of fewer, larger diameter, muscle skeletal fibres to reach a given body size. In order to better understand the genetic mechanisms behind these different patterns of muscle growth and to investigate how the decoupling of Gh and nutritional signals affects gene regulation we used RNA-seq to compare the fast skeletal muscle transcriptome in TR and WT coho salmon...
2015: BMC Genomics
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