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https://www.readbyqxmd.com/read/29301754/maintenance-of-murine-platelet-homeostasis-by-the-kinase-csk-and-the-phosphatase-cd148
#1
Jun Mori, Zoltan Nagy, Giada Di Nunzio, Christopher W Smith, Mitchell J Geer, Rashid Al Ghaithi, Johanna P van Geffen, Silke Heising, Luke Boothman, Bibian M E Tullemans, Joao N Correia, Louise Tee, Marijke J E Kuijpers, Paul Harrison, Johan W M Heemskerk, Gavin E Jarvis, Alexander Tarakhovsky, Arthur Weiss, Alexandra Mazharian, Yotis A Senis
Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, however it remains unclear how they are regulated. Here we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury, rather than a prothrombotic phenotype...
January 4, 2018: Blood
https://www.readbyqxmd.com/read/29248956/human-c-src-kinase-csk-overexpression-makes-t-cells-dummy
#2
Else Marit Inderberg, Nadia Mensali, Morten P Oksvold, Lars-Egil Fallang, Anne Fåne, Gjertrud Skorstad, Grethe-Elisabeth Stenvik, Cinzia Progida, Oddmund Bakke, Gunnar Kvalheim, June H Myklebust, Sébastien Wälchli
Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide-MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell...
December 16, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29167383/c-terminal-src-kinase-csk-regulates-the-tricellular-junction-protein-gliotactin-independent-of-src
#3
G D N Gayathri Samarasekera, Vanessa Jane Auld
Tricellular junctions (TCJs) are uniquely placed permeability barriers formed at the corners of polarized epithelia where tight junctions (TJ) in vertebrates or septate junctions (SJ) in invertebrates from three cells converge. Gliotactin is a Drosophila TCJ protein and loss of Gliotactin results in SJ and TCJ breakdown, and permeability barrier loss. When overexpressed, Gliotactin spreads away from the TCJs resulting in disrupted epithelial architecture including over-proliferation, cell delamination and migration...
November 22, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29079189/upregulation-of-pag1-cbp-contributes-to-adipose-derived-mesenchymal-stem-cells-promoted-tumor-progression-and-chemoresistance-in-breast-cancer
#4
Yunshu Lu, Yipeng Yang, Yan Liu, Yajuan Hao, Yijian Zhang, Yunping Hu, Lin Jiang, Yurong Gong, Kejin Wu, Yingbin Liu
C-terminal Src kinase (Csk)-binding protein (Cbp) is a ubiquitously expressed transmembrane adaptor protein which regulating Src family kinase (SFK) activities. Although SFKs are well known for their involvement in breast cancer, the function of Cbp in breast carcinogenesis upon the adipose-tumor microenvironment has not been investigated. Here, we reported that adipose-derived mesenchymal stem cells (ASCs) induced increased expression of Cbp accompanied by enhanced cell proliferation and chemotherapy resistance in breast cancer cell MCF-7/ADR...
October 24, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28974561/crk-tyrosine-phosphorylation-regulates-pdgf-bb-inducible-src-activation-and-breast-tumorigenicity-and-metastasis
#5
Sushil Kumar, Bin Lu, Viralkumar Davra, Peter Hornbeck, Kazuya Machida, Raymond B Birge
The activity of Src family kinases (Src being the prototypical member) is tightly regulated by differential phosphorylation on Tyr416 (positive) and Tyr527 (negative), a duet that reciprocally regulates kinase activity. The latter negative regulation of Src on Tyr527 is mediated by C-terminal Src kinase (CSK) that phosphorylates Tyr527 and maintains Src in a clamped negative regulated state by promoting an intra-molecular association. Here it is demonstrated that the SH2- and SH3-domain containing adaptor protein CrkII, by virtue of its phosphorylation on Tyr239, regulates the Csk/Src signaling axis to control Src activation...
October 3, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28939764/early-emergence-of-negative-regulation-of-the-tyrosine-kinase-src-by-the-c-terminal-src-kinase
#6
Barbara Taskinen, Evandro Ferrada, Douglas M Fowler
Stringent regulation of tyrosine kinase activity is essential for normal cellular function. In humans, the tyrosine kinase Src is inhibited via phosphorylation of its C-terminal tail by another kinase, C-terminal Src kinase (Csk). Although Src and Csk orthologs are present across holozoan organisms, including animals and protists, the Csk-Src negative regulatory mechanism appears to have evolved gradually. For example, in choanoflagellates, Src and Csk are both active, but the negative regulatory mechanism is reportedly absent...
November 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28874816/protein-tyrosine-phosphatase-non-receptor-22-and-c-src-tyrosine-kinase-genes-are-down-regulated-in-patients-with-rheumatoid-arthritis
#7
Sara Remuzgo-Martínez, Fernanda Genre, Santos Castañeda, Alfonso Corrales, Pablo Moreno-Fresneda, Begoña Ubilla, Verónica Mijares, Virginia Portilla, Jesús González-Vela, Trinitario Pina, Gonzalo Ocejo-Vinyals, Juan Irure-Ventura, Ricardo Blanco, Javier Martín, Javier Llorca, Raquel López-Mejías, Miguel A González-Gay
Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility. Nevertheless, its potential influence on PTPN22 expression in RA has not been completely elucidated. Furthermore, PTPN22 binds to C-Src tyrosine kinase (CSK) forming a key complex in autoimmunity. However, the information of CSK gene in RA is scarce. In this study, we analyzed the relative PTPN22 and CSK expression in peripheral blood from 89 RA patients and 43 controls to determine if the most relevant PTPN22 (rs2488457, rs2476601 and rs33996649) and CSK (rs34933034 and rs1378942) polymorphisms may influence on PTPN22 and CSK expression in RA...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28768887/phosphotyrosine-signalling-and-the-origin-of-animal-multicellularity
#8
Kai Tong, Yuyu Wang, Zhixi Su
The evolution of multicellular animals (i.e. metazoans) from a unicellular ancestor is one of the most important yet least understood evolutionary transitions. Historically, given its indispensable functions in intercellular communication and exclusive presence in metazoans, phosphotyrosine (pTyr) signalling was considered a metazoan-specific evolutionary innovation that might have contributed to the origin of metazoan multicellularity. However, recent studies have led to a new understanding of pTyr signalling evolution and its role in the metazoan origin...
August 16, 2017: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/28724838/csk-regulates-blood-pressure-by-controlling-the-synthetic-pathways-of-aldosterone
#9
Sung-Moon Kim, Ji-One Kang, Ji Eun Lim, Sue-Yun Hwang, Bermseok Oh
BACKGROUND: Blood pressure is regulated by a network of diverse physiological pathways. The C-terminal Src kinase (CSK) locus (15q24) is associated with blood pressure in various ethnic groups. It was recently reported thatCskinsufficiency increases blood pressure through Src. The mechanisms of hypertension inCsk(+/-)mice are examined further in this study.Methods and Results:To identify a causal component responsible for hypertension inCsk(+/-), the heart rate was measured by electrocardiogram and plasma volume by Evans blue dilution...
July 20, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/28522807/traf3-enhances-tcr-signaling-by-regulating-the-inhibitors-csk-and-ptpn22
#10
Alicia M Wallis, Ellie C Wallace, Bruce S Hostager, Zuoan Yi, Jon C D Houtman, Gail A Bishop
The adaptor protein TNF receptor associated factor (TRAF) 3 is required for effective TCR signaling and normal T cell effector functions, and associates with the CD3/CD28 complex upon activation. To determine how TRAF3 promotes proximal TCR signaling, we studied TRAF3-deficient mouse and human T cells, which showed a marked reduction in activating phosphorylation of the TCR-associated kinase Lck. The impact of TRAF3 on this very early signaling event led to the hypothesis that TRAF3 restrains one or both of two known inhibitors of Lck, C-terminal Src kinase (Csk) and protein tyrosine phosphatase N22 (PTPN22)...
May 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28508421/subversion-of-host-kinases-a-key-network-in-cellular-signaling-hijacked-by-helicobacter-pylori-caga
#11
REVIEW
Nicole Tegtmeyer, Matthias Neddermann, Carmen Isabell Asche, Steffen Backert
Helicobacter pylori is a paradigm of persistent pathogens and major risk factor for developing severe diseases including adenocarcinoma in the human stomach. An important bacterial factor linked to gastric disease progression is the cag pathogenicity island-encoded type-IV secretion system (T4SS) effector protein CagA. Translocated CagA undergoes tyrosine phosphorylation at EPIYA-motifs and then activates or inactivates multiple host signaling proteins in a phosphorylation-dependent and phosphorylation-independent fashion...
May 15, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28393242/overexpression-of-srcin1-contributes-to-the-growth-and-metastasis-of-colorectal-cancer
#12
Mengnan Zhang, Feng Ma, Ruyi Xie, Yao Wu, Meiyan Wu, Pei Zhang, Ying Peng, Jinjun Zhao, Jing Xiong, Aimin Li, Cheng Kequan, Yali Zhang, Side Liu, Jide Wang, Xueqing Chen
The adaptor protein Srcin1 is a novel Src-binding protein that regulates Src activation through C-terminal Src kinase (Csk). Srcin1 behaves as a tumour suppressor in breast cancer, but the role of Srcin1 in the development of colorectal cancer (CRC) remains unknown. In the present study, Srcin1 expression in normal tissue was examined by tissue microarray and assessed by immunohistochemistry in 10 patients. In addition, the biological impact of Srcin1 knockdown on CRC cells was investigated in vitro and in vivo...
May 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28178691/p-glycoprotein-attenuates-dna-repair-activity-in-multidrug-resistant-cells-by-acting-through-the-cbp-csk-src-cascade
#13
Li-Fang Lin, Ming-Hsi Wu, Vijaya Kumar Pidugu, I-Ching Ho, Tsann-Long Su, Te-Chang Lee
Recent studies have demonstrated that P-glycoprotein (P-gp) expression impairs DNA interstrand cross-linking agent-induced DNA repair efficiency in multidrug-resistant (MDR) cells. To date, the detailed molecular mechanisms underlying how P-gp interferes with Src activation and subsequent DNA repair activity remain unclear. In this study, we determined that the C-terminal Src kinase-binding protein (Cbp) signaling pathway involved in the negative control of Src activation is enhanced in MDR cells. We also demonstrated that cells that ectopically express P-gp exhibit reduced activation of DNA damage response regulators, such as ATM, Chk2, Braca1 and Nbs1 and hence attenuated DNA double-strand break repair capacity and become more susceptible than vector control cells to DNA interstrand cross-linking (ICL) agents...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28098256/dopamine-promotes-nmda-receptor-hypofunction-in-the-retina-through-d1-receptor-mediated-csk-activation-src-inhibition-and-decrease-of-glun2b-phosphorylation
#14
Renato Socodato, Felipe N Santiago, Camila C Portugal, Ivan Domith, Thaísa G Encarnação, Erick C Loiola, Ana L M Ventura, Marcelo Cossenza, João B Relvas, Newton G Castro, Roberto Paes-de-Carvalho
Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D1 receptors (D1Rs) and the cytosolic protein tyrosine kinase Src can, independently, modulate the behavior of NMDA-type glutamate receptors (NMDARs). Here we studied the interplay between D1Rs, Src and NMDARs in retinal neurons. We reveal that dopamine-mediated D1R stimulation provoked NMDAR hypofunction in retinal neurons by attenuating NMDA-gated currents, by preventing NMDA-elicited calcium mobilization and by decreasing the phosphorylation of NMDAR subunit GluN2B...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27926878/the-csk-associated-adaptor-pag-inhibits-effector-t-cell-activation-in-cooperation-with-phosphatase-ptpn22-and-dok-adaptors
#15
Dominique Davidson, Ming-Chao Zhong, Pier Paolo Pandolfi, Silvia Bolland, Ramnik J Xavier, Brian Seed, Xin Li, Hua Gu, André Veillette
The transmembrane adaptor PAG (Cbp) has been proposed to mediate membrane recruitment of Csk, a cytoplasmic protein tyrosine kinase playing a critical inhibitory role during T cell activation, by inactivating membrane-associated Src kinases. However, this model has not been validated by genetic evidence. Here, we demonstrate that PAG-deficient mice display enhanced T cell activation responses in effector, but not in naive, T cells. PAG-deficient mice also have augmented T cell-dependent autoimmunity and greater resistance to T cell anergy...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27875633/design-synthesis-and-evaluation-of-dasatinib-amino-acid-and-dasatinib-fatty-acid-conjugates-as-protein-tyrosine-kinase-inhibitors
#16
Rakesh K Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady Verkhivker, Keykavous Parang, Gongqin Sun
Derivatives of the tyrosine kinase inhibitor dasatinib were synthesized by esterification with 25 carboxylic acids, including amino acids and fatty acids, thereby extending the drug to interact with more diverse sites and to improve specificity. The dasatinib-l-arginine derivative (Das-R, 7) was found to be the most potent of the inhibitors tested, with IC50 values of 4.4, <0.25, and <0.45 nm against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das-C10 ) with an IC50 value of 3...
January 5, 2017: ChemMedChem
https://www.readbyqxmd.com/read/27819029/combining-biophysical-methods-to-analyze-the-disulfide-bond-in-sh2-domain-of-c-terminal-src-kinase
#17
Dongsheng Liu, David Cowburn
The Src Homology 2 (SH2) domain is a structurally conserved protein domain that typically binds to a phosphorylated tyrosine in a peptide motif from the target protein. The SH2 domain of C-terminal Src kinase (Csk) contains a single disulfide bond, which is unusual for most SH2 domains. Although the global motion of SH2 domain regulates Csk function, little is known about the relationship between the disulfide bond and binding of the ligand. In this study, we combined X-ray crystallography, solution NMR, and other biophysical methods to reveal the interaction network in Csk...
2016: Biophysics Reports
https://www.readbyqxmd.com/read/27765068/genome-wide-methylation-profiling-of-ovarian-cancer-patient-derived-xenografts-treated-with-the-demethylating-agent-decitabine-identifies-novel-epigenetically-regulated-genes-and-pathways
#18
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
https://www.readbyqxmd.com/read/27603666/src-family-kinases-modulate-the-loss-of-endothelial-barrier-function-in-response-to-tnf-%C3%AE-crosstalk-with-p38-signaling
#19
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
https://www.readbyqxmd.com/read/27550814/role-of-src-family-kinases-in-regulation-of-intestinal-epithelial-homeostasis
#20
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
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