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csk src

Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Alejandro P Adam, Anthony M Lowery, Nina Martino, Hiba Alsaffar, Peter A Vincent
Activation of Src Family Kinase (SFK) signaling is required for the increase in endothelial permeability induced by a variety of cytokines and growth factors. However, we previously demonstrated that activation of endogenous SFKs by expression of dominant negative C-terminal Src Kinase (DN-Csk) is not sufficient to decrease endothelial adherens junction integrity. Basal SFK activity has been observed in normal venular endothelia and was not associated with increased basal permeability. The basal SFK activity however was found to contribute to increased sensitivity of the venular endothelium to inflammatory mediator-induced leakage...
2016: PloS One
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
Lu Xu, Xin Tong, Sujie Zhang, Fan Yin, Xiaoyan Li, Huafeng Wei, Cheng Li, Yajun Guo, Jian Zhao
Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients' prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice...
July 29, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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
Ana González-Sánchez, Myriam Jaraíz-Rodríguez, Marta Domínguez-Prieto, Sandra Herrero-González, José M Medina, Arantxa Tabernero
Connexin43 (Cx43), the major protein forming gap junctions in astrocytes, is reduced in high-grade gliomas, where its ectopic expression exerts important effects, including the inhibition of the proto-oncogene tyrosine-protein kinase Src (c-Src). In this work we aimed to investigate the mechanism responsible for this effect. The inhibition of c-Src requires phosphorylation at tyrosine 527 mediated by C-terminal Src kinase (Csk) and dephosphorylation at tyrosine 416 mediated by phosphatases, such as phosphatase and tensin homolog (PTEN)...
July 6, 2016: Oncotarget
Lu Zhang, Zhilong Ren, Qian Yang, Guohua Ding
Increasing data have shown that angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. The mechanism underlying Ang II-induced podocyte apoptosis has not been established. C-terminal Src kinase (Csk) is a cytoplasmic kinase that interacts with scaffolding proteins involved in cell growth, adhesion, and polarization, and the role of Csk in regulating cellular apoptosis has gradually attracted attention. This study evaluates the role of Csk in Ang II-induced podocyte apoptosis...
July 2016: Apoptosis: An International Journal on Programmed Cell Death
Yoshie Senda, Naoko Murata-Kamiya, Masanori Hatakeyama
Pragmin is one of the few mammalian proteins containing the Glu-Pro-Ile-Tyr-Ala (EPIYA) tyrosine-phosphorylation motif that was originally discovered in the Helicobacter pylori CagA oncoprotein. Following delivery into gastric epithelial cells by type IV secretion and subsequent tyrosine phosphorylation at the EPIYA motifs, CagA serves as an oncogenic scaffold/adaptor that promiscuously interacts with SH2 domain-containing mammalian proteins such as the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) and the C-terminal Src kinase (Csk), a negative regulator of Src family kinases...
July 2016: Cancer Science
Saurabh Agarwal, Rajib Ghosh, Zaowen Chen, Anna Lakoma, Preethi H Gunaratne, Eugene S Kim, Jason M Shohet
Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with high mortality rates. The tyrosine kinase c-Src has been known to play an important role in differentiation of NB cells, but the mechanism of c-Src regulation has not been defined. Here, we characterize PAG1 (Cbp, Csk binding protein), a central inhibitor of c-Src and other Src family kinases, as a novel tumor suppressor in NB. Clinical cohort analysis demonstrate that low expression of PAG1 is a significant prognostic factor for high stage disease, increased relapse, and worse overall survival for children with NB...
April 26, 2016: Oncotarget
Ashlyn M Spring, Douglas J Brusich, C Andrew Frank
Forms of homeostatic plasticity stabilize neuronal outputs and promote physiologically favorable synapse function. A well-studied homeostatic system operates at the Drosophila melanogaster larval neuromuscular junction (NMJ). At the NMJ, impairment of postsynaptic glutamate receptor activity is offset by a compensatory increase in presynaptic neurotransmitter release. We aim to elucidate how this process operates on a molecular level and is preserved throughout development. In this study, we identified a tyrosine kinase-driven signaling system that sustains homeostatic control of NMJ function...
February 2016: PLoS Genetics
Xin-Tai Wang, Rui Zheng, Zhan-Wei Suo, Yan-Ni Liu, Zi-Yang Zhang, Zheng-An Ma, Ye Xue, Man Xue, Xian Yang, Xiao-Dong Hu
The enzymatic activity of protein tyrosine kinase Src is subjected to the regulation by C-terminal Src kinase (CSK) and protein tyrosine phosphatases (PTPs). Aberrant Src activation in the spinal cord dorsal horn is pivotal for the induction and development of nociceptive behavioral sensitization. In this study, we found that paxillin, one of the well-characterized cell adhesion components involved in cell migration and survival, integrated CSK and PTPs' signaling to regulate Src-dependent nociceptive plasticity...
March 2016: Pain
Mai Usui, Masaharu Uno, Eisuke Nishida
Brown adipocytes and beige adipocytes can expend energy, generate heat, and increase whole-body energy expenditure. The detailed mechanisms of adipogenesis and thermogenesis of these cells are still obscure. Here, we show that Src family kinases (SFKs) regulate both brown adipogenesis and browning of white adipocytes. To identify factors involved in brown adipogenesis, we first examined the effect of several chemical inhibitors on the differentiation of brown preadipocytes isolated from mouse brown adipose tissue (BAT) and found that treatment with PP2, the specific inhibitor of SFKs, promoted the differentiation...
April 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Jianhui Li, Yahui Li, Hua He, Chengbo Liu, Wen Li, Lijuan Xie, Yongjun Zhang
Bronchopulmonary dysplasia (BPD) is characterized by premature alveolar developmental arrest. Antenatal exposure to inflammation inhibits lung morphogenesis, thus increasing the risk of developing BPD. Alveolar myofibroblasts are thought to migrate into the septal tips and elongate secondary septa during alveolarization. Here we found lipopolysaccharide (LPS) disrupted the directional migration of myofibroblasts and increased actin stress fiber expression and focal adhesion formation. In addition, COOH-terminal Src kinase (Csk) activity was downregulated in myofibroblasts treated with LPS, while activation of Src or epidermal growth factor receptor (EGFR) was upregulated by LPS treatment...
March 15, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Hyeon-Ju Lee, Ji-One Kang, Sung-Moon Kim, Su-Min Ji, So-Yon Park, Marina E Kim, Baigalmaa Jigden, Ji Eun Lim, Sue-Yun Hwang, Young-Ho Lee, Bermseok Oh
OBJECTIVE: Recent genome-wide association studies have identified 33 human genetic loci that influence blood pressure. The 15q24 locus is one such locus that has been confirmed in Asians and Europeans. There are 21 genes in the locus within a 1-Mb boundary, but a functional link of these genes to blood pressure has not been reported. We aimed to identify a causative gene for blood pressure change in the 15q24 locus. METHODS AND RESULTS: CSK and ULK3 were selected as candidate genes based on eQTL analysis studies that showed the association between gene transcript levels and the lead SNP (rs1378942)...
2016: PloS One
Yanli Liu, Johnathan Lau, Weiguo Li, Wolfram Tempel, Li Li, Aiping Dong, Ashrut Narula, Su Qin, Jinrong Min
TXNIP (thioredoxin-interacting protein) negatively regulates the antioxidative activity of thioredoxin and participates in pleiotropic cellular processes. Its deregulation is linked to various human diseases, including diabetes, acute myeloid leukaemia and cardiovascular diseases. The E3 ubiquitin ligase Itch (Itchy homologue) polyubiquitinates TXNIP to promote its degradation via the ubiquitin-proteasome pathway, and this Itch-mediated polyubiquitination of TXNIP is dependent on the interaction of the four WW domains of Itch with the two PPxY motifs of TXNIP...
January 15, 2016: Biochemical Journal
Tanya S Freedman, Ying X Tan, Katarzyna M Skrzypczynska, Boryana N Manz, Frances V Sjaastad, Helen S Goodridge, Clifford A Lowell, Arthur Weiss
Clustering of receptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs) initiates the macrophage antimicrobial response. ITAM receptors engage Src-family tyrosine kinases (SFKs) to initiate phagocytosis and macrophage activation. Macrophages also encounter nonpathogenic molecules that cluster receptors weakly and must tune their sensitivity to avoid inappropriate responses. To investigate this response threshold, we compared signaling in the presence and absence of receptor clustering using a small-molecule inhibitor of Csk, which increased SFK activation and produced robust membrane-proximal signaling...
October 30, 2015: ELife
Kavita Reginald, Karima Chaoui, Romain Roncagalli, Mathilde Beau, Marisa Goncalves Menoita, Bernard Monsarrat, Odile Burlet-Schiltz, Marie Malissen, Anne Gonzalez de Peredo, Bernard Malissen
The protein tyrosine kinase LCK plays a key role in TCR signaling, and its activity is dynamically controlled by the tyrosine kinase C-terminal Src kinase (CSK) and the tyrosine phosphatase CD45. CSK is brought in contiguity to LCK via binding to a transmembrane adaptor known as phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG). The lack of a blatant phenotype in PAG-deficient mice has impeded our understanding of the mechanisms through which PAG exerts its negative-regulatory role in TCR signaling...
December 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Raquel López-Mejías, Fernanda Genre, Sara Remuzgo-Martínez, Belén Sevilla Pérez, Santos Castañeda, Javier Llorca, Norberto Ortego-Centeno, Begoña Ubilla, Verónica Mijares, Trinitario Pina, Vanesa Calvo-Río, Natalia Palmou, José A Miranda-Filloy, Antonio Navas Parejo, Diego Argila, Javier Sánchez-Pérez, Esteban Rubio, Manuel León Luque, Juan María Blanco-Madrigal, Eva Galíndez-Aguirregoikoa, J Gonzalo Ocejo-Vinyals, Javier Martín, Ricardo Blanco, Miguel A González-Gay
INTRODUCTION: To determine whether the PTPN22 (protein tyrosine phosphatase nonreceptor 22)/CSK (c-src tyrosine kinase) pathway is implicated in the susceptibility and clinical heterogeneity of Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: A set of 329 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria and 515 sex and ethnically matched controls were recruited in this study...
2015: Arthritis Research & Therapy
Ales Drobek, Jarmila Kralova, Tereza Skopcova, Marketa Kucova, Petr Novák, Pavla Angelisová, Pavel Otahal, Meritxell Alberich-Jorda, Tomas Brdicka
Mutations in the adaptor protein PSTPIP2 are the cause of the autoinflammatory disease chronic multifocal osteomyelitis in mice. This disease closely resembles the human disorder chronic recurrent multifocal osteomyelitis, characterized by sterile inflammation of the bones and often associated with inflammation in other organs, such as the skin. The most critical process in the disease's development is the enhanced production of IL-1β. This excessive IL-1β is likely produced by neutrophils. In addition, the increased activity of macrophages, osteoclasts, and megakaryocytes has also been described...
October 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Boryana N Manz, Ying Xim Tan, Adam H Courtney, Florentine Rutaganira, Ed Palmer, Kevan M Shokat, Arthur Weiss
The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinases (SFK), plays a crucial role in controlling basal and inducible receptor signaling. To investigate how Csk activity regulates T cell antigen receptor (TCR) signaling, we utilized a mouse expressing mutated Csk (Csk(AS)) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of Csk(AS) during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation...
2015: ELife
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