Phospholipase C gamma 2 tyrosine

Phillip N Key, Joe Germino, Liping Yang, Sytse J Piersma, Sandeep K Tripathy
Natural killer (NK) cells play an important role in the innate immune response. The summation of activation and inhibitory signals delivered through cell surface membrane receptors determines NK cell function. However, the continuous engagement of an activating receptor on NK cells appears to render the cells hyporesponsive to stimulation through other unrelated activating receptors. The mechanism by which this takes place remains unclear. Herein we demonstrate that continuous in vivo engagement of the Ly49H receptor with its ligand, m157, results in Ly49H+ NK cells that are hyporesponsive to further stimulation by other ITAM-dependent and independent receptors, while Ly49H- NK cells remain unaffected...
2019: Frontiers in Immunology
Limor Parker, Hilla Bahat, Michael Y Appel, Dina Volodarsky Baum, Relly Forer, Nir Pillar, Michael Goldberg, Michael Goldman
BACKGROUND: Familial steroid-sensitive nephrotic syndrome (SSNS) is rare, complicating the identification of candidate genes. A recent population-based approach study of SSNS identified HLA-DQA1 and phospholipase C-gamma 2 (PLCG2) missense coding variants as candidate loci. PLCG2 is a signaling molecule regulated by phosphorylation and is critical for Ca2+ flux in cells of the immune system. PATIENTS AND METHODS: In order to detect a candidate gene for familial SSNS, we conducted an whole-exome sequencing in a pedigree consisting of two healthy parents, two non-identical twin brothers with SSNS, and a healthy young sibling...
December 19, 2018: Pediatric Research
Rashmi Kanagal-Shamanna, Preetesh Jain, Keyur P Patel, Mark Routbort, Carlos Bueso-Ramos, Tahani Alhalouli, Joseph D Khoury, Rajyalakshmi Luthra, Alessandra Ferrajoli, Michael Keating, Nitin Jain, Jan Burger, Zeev Estrov, William Wierda, Hagop M Kantarjian, L Jeffrey Medeiros
BACKGROUND: In a proportion of patients with chronic lymphocytic leukemia (CLL), resistance to Bruton tyrosine kinase (BTK) inhibitors (BTKi) is attributed to acquired BTK/phospholipase C gamma 2 (PLCG2) mutations. However, knowledge regarding additional genetic lesions associated with BTK/PLCG2 mutations, and gene mutations in patients lacking BTK/PLCG2 mutations, is limited. METHODS: Using targeted deep sequencing, mutations in 29 genes associated with CLL and/or the BCR signaling pathway were assessed in patients with CLL who developed resistance to BTK inhibition with ibrutinib/acalabrutinib at a single institution...
December 3, 2018: Cancer
Jong Min Baek, Yoon-Hee Cheon, Sung Chul Kwak, Hong Young Jun, Kwon-Ha Yoon, Myeung Su Lee, Ju-Young Kim
Claudins (Cldns) are well-established components of tight junctions (TJs) that play a pivotal role in the modulation of paracellular permeability. Several studies have explored the physiologic aspects of Cldn family members in bone metabolism. However, the effect of Cldn11, a major component of central nervous system myelin, on bone homeostasis has not been reported. In this study, we demonstrate that Cldn11 is a potential target for bone disease therapeutics as a dual modulator of osteogenesis enhancement and osteoclastogenesis inhibition...
April 27, 2018: Experimental & Molecular Medicine
Devin L Wakefield, David Holowka, Barbara Baird
We examined the spatial targeting of early and downstream signaling mediated by the IgE receptor (FcεRI) in RBL mast cells utilizing surface-patterned 2,4 dinitrophenyl (DNP) ligands. Micron-sized features of DNP are presented as densely immobilized conjugates of bovine serum albumin (DNP-BSA) or mobile in a supported lipid bilayer (DNP-SLB). Although soluble anti-DNP IgE binds uniformly across features for both pattern types, IgE bound to FcεRI on cells shows distinctive distributions: uniform for DNP-SLB and edge-concentrated for DNP-BSA...
August 9, 2017: Molecular Biology of the Cell
Michael Leist, Susanne Rinné, Maia Datunashvili, Ania Aissaoui, Hans-Christian Pape, Niels Decher, Sven G Meuth, Thomas Budde
KEY POINTS: The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K+ currents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK-1 K+ channels results in hyperpolarization of interneurons and suppression of their action potential firing...
September 1, 2017: Journal of Physiology
Adam Albitar, Wanlong Ma, Ivan DeDios, Jeffrey Estella, Inhye Ahn, Mohammed Farooqui, Adrian Wiestner, Maher Albitar
Patients with chronic lymphocytic leukemia (CLL) that develop resistance to Bruton tyrosine kinase (BTK) inhibitors are typically positive for mutations in BTK or phospholipase c gamma 2 (PLCγ2). We developed a high sensitivity (HS) assay utilizing wild-type blocking polymerase chain reaction achieved via bridged and locked nucleic acids. We used this high sensitivity assay in combination with Sanger sequencing and next generation sequencing (NGS) and tested cellular DNA and cell-free DNA (cfDNA) from patients with CLL treated with the BTK inhibitor, ibrutinib...
March 14, 2017: Oncotarget
Soo Ji Woo, Hyae In Jo, Hyung Ho Lee, Joon Ki Chung
Phospholipase C gamma 1 and gamma 2 (PLCG1 and PLCG2) are influential in modulating Ca(2+) and diacylglycerol, second messengers involved in tyrosine kinase-dependent signaling, including growth factor activation. Here, we used RACE (rapid amplification of cDNA ends) to clone cDNA encoding PLCG1 (PoPLCG1) and PLCG2 (PoPLCG2) in the olive flounder (Paralichthys olivaceus). The respective 1313 and 1249 amino acid sequences share high identity with human PLCG1 and PLCG2, and contain the following domains: pleckstrin homology (PH), EF-hand, catalytic X and Y, Src homology 2 (SH2), Src homology 3 (SH3), and C2...
April 2017: Fish & Shellfish Immunology
Fengfeng Wang, Fei Meng, Lili Wang, S C Cesar Wong, William C S Cho, Lawrence W C Chan
Lung cancer is the top cancer killer worldwide with high mortality rate. Majority belong to non-small cell lung cancers (NSCLCs). The epidermal growth factor receptor (EGFR) has been broadly explored as a drug target for therapy. However, the drug responses are not durable due to the acquired resistance. MicroRNAs (miRNAs) are small non-coding and endogenous molecules that can inhibit mRNA translation initiation and degrade mRNAs. We wonder if some downstream molecules shared by EGFR and the other tyrosine kinase receptors (TKRs) further transduce the signals alternatively, and some miRNAs play the key roles in affecting the expression of these downstream molecules...
2016: Frontiers in Genetics
Ana Saavedra, Mar Puigdellívol, Shiraz Tyebji, Pradeep Kurup, Jian Xu, Silvia Ginés, Jordi Alberch, Paul J Lombroso, Esther Pérez-Navarro
Brain-derived neurotrophic factor (BDNF) promotes synaptic strengthening through the regulation of kinase and phosphatase activity. Conversely, striatal-enriched protein tyrosine phosphatase (STEP) opposes synaptic strengthening through inactivation or internalization of signaling molecules. Here, we investigated whether BDNF regulates STEP levels/activity. BDNF induced a reduction of STEP61 levels in primary cortical neurons, an effect that was prevented by inhibition of tyrosine kinases, phospholipase C gamma, or the ubiquitin-proteasome system (UPS)...
August 2016: Molecular Neurobiology
Ta-Ming Liu, Jennifer A Woyach, Yiming Zhong, Arletta Lozanski, Gerard Lozanski, Shuai Dong, Ethan Strattan, Amy Lehman, Xiaoli Zhang, Jeffrey A Jones, Joseph Flynn, Leslie A Andritsos, Kami Maddocks, Samantha M Jaglowski, Kristie A Blum, John C Byrd, Jason A Dubovsky, Amy J Johnson
Ibrutinib has significantly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Recent reports attribute ibrutinib resistance to acquired mutations in Bruton agammaglobulinemia tyrosine kinase (BTK), the target of ibrutinib, as well as the immediate downstream effector phospholipase C, γ2 (PLCG2). Although the C481S mutation found in BTK has been shown to disable ibrutinib's capacity to irreversibly bind this primary target, the detailed mechanisms of mutations in PLCG2 have yet to be established...
July 2, 2015: Blood
T M Schnöder, P Arreba-Tutusaus, I Griehl, L Bullinger, M Buschbeck, S W Lane, K Döhner, C Plass, D B Lipka, F H Heidel, T Fischer
Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells (HSCs) into more committed progenitors and finally into erythrocytes. Binding of erythropoietin (Epo) to its receptor (EpoR) is required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Janus kinase 2 (Jak2) tyrosine kinase and Stat5a/b as a central pathway...
June 2015: Cell Death and Differentiation
Susan Li, Christine H Miller, Eugenia Giannopoulou, Xiaoyu Hu, Lionel B Ivashkiv, Baohong Zhao
Osteoclastogenesis requires activation of RANK signaling as well as costimulatory signals from immunoreceptor tyrosine-based activation motif-containing (ITAM-containing) receptors/adaptors, predominantly tyrosine kinase-binding proteins DAP12 and FcRγ, in osteoclast precursors. It is not well understood how costimulatory signals are regulated and integrated with RANK signaling. Here, we found that osteopetrotic bone phenotypes in mice lacking DAP12 or DAP12 and FcRγ are mediated by the transcription factor RBP-J, as deletion of Rbpj in these mice substantially rescued the defects of bone remodeling...
November 2014: Journal of Clinical Investigation
Corinna Lehnert, Maxi Weiswange, Irmela Jeremias, Carina Bayer, Michaela Grunert, Klaus-Michael Debatin, Gudrun Strauss
The TRAIL-receptor/TRAIL system originally described to induce apoptosis preferentially in malignant cells is also known to be involved in T cell homeostasis and the response to viral infections and autoimmune diseases. Whereas the expression of TRAIL on activated NK and T cells increases their cytotoxicity, induction of TRAIL on APCs can turn them into apoptosis inducers but might also change their immunostimulatory capacity. Therefore, we analyzed how TRAIL-receptor (TRAIL-R) costimulation is modulating TCR-mediated activation of human T cells...
October 15, 2014: Journal of Immunology
Musaed M Alshahrani, Eunice Yang, Jana Yip, Simona S Ghanem, Simon L Abdallah, Anthony M deAngelis, Cindy J O'Malley, Fatemeh Moheimani, Sonia M Najjar, Denise E Jackson
Carcinoembryonic antigen-related cell adhesion molecule-2 (CEACAM2) is a cell-surface glycoprotein expressed on blood, epithelial, and vascular cells. CEACAM2 possesses adhesive and signaling properties mediated by immunoreceptor tyrosine-based inhibitory motifs. In this study, we demonstrate that CEACAM2 is expressed on the surface and in intracellular pools of platelets. Functional studies of platelets from Ceacam2(-/-)-deficient mice (Cc2(-/-)) revealed that CEACAM2 serves to negatively regulate collagen glycoprotein VI (platelet) (GPVI)-FcRγ-chain and the C-type lectinlike receptor 2 (CLEC-2) signaling...
October 9, 2014: Blood
R Wang, P Zhang, Y Wang, L Zhang
OBJECTIVE: This study aimed to examine the mechanism of Tα146-162-iMDC in the pathogenic intervention of mice with experimental autoimmune myasthenia gravis (EAMG) from the perspective of B-cell activation. MATERIALS AND METHODS: The mice were divided into three groups, model (A), intervention (B), and control (C), with the intervention of Tα146-162-iMDC. The expressions of Cbl-b mRNA, Syk, Lyn, Btk, and phospholipase C (PLC)-γ2 proteins and their phosphorylated proteins were detected...
2014: European Review for Medical and Pharmacological Sciences
Jennifer A Woyach, Richard R Furman, Ta-Ming Liu, Hatice Gulcin Ozer, Marc Zapatka, Amy S Ruppert, Ling Xue, Daniel Hsieh-Hsin Li, Susanne M Steggerda, Matthias Versele, Sandeep S Dave, Jenny Zhang, Ayse Selen Yilmaz, Samantha M Jaglowski, Kristie A Blum, Arletta Lozanski, Gerard Lozanski, Danelle F James, Jacqueline C Barrientos, Peter Lichter, Stephan Stilgenbauer, Joseph J Buggy, Betty Y Chang, Amy J Johnson, John C Byrd
BACKGROUND: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance...
June 12, 2014: New England Journal of Medicine
Wei-Zhong Ying, Kristal J Aaron, Paul W Sanders
The amount of Na(+) and K(+) in the diet promotes significant changes in endothelial cell function. In the present study, a series of in vitro and in vivo experiments determined the role of Na(+) and K(+) in the regulation of two pleckstrin homology domain-containing intracellular signaling molecules, phospholipase C (PLC)-γ1 and epithelial and endothelial tyrosine kinase/bone marrow tyrosine kinase on chromosome X (Bmx), and agonist-generated Ca(2+) signaling in the endothelium. Extracellular K(+) concentration regulated the levels of activated PLC-γ1, Bmx, and carbachol-stimulated intracellular Ca(2+) mobilization in human endothelial cells...
July 1, 2014: American Journal of Physiology. Renal Physiology
Wen Liu, Mei-Juan Cai, Chuan-Chuan Zheng, Jin-Xing Wang, Xiao-Fan Zhao
In addition to the classical nuclear receptor pathway, there is a nongenomic pathway in the cell membrane that regulates gene expression in animal steroid hormone signaling; however, this mechanism is unclear. Here, we report that the insect steroid hormone 20-hydroxyecdysone (20E) regulates calcium influx via phospholipase Cγ1 (PLCG1) to modulate the protein kinase C phosphorylation of the transcription factor ultraspiracle (USP1) in the lepidopteran insect Helicoverpa armigera. The PLCG1 mRNA levels are increased during the molting and metamorphic stages...
May 9, 2014: Journal of Biological Chemistry
Luis-Alberto Pérez-Quintero, Romain Roncagalli, Huaijian Guo, Sylvain Latour, Dominique Davidson, André Veillette
Ewing's sarcoma-associated transcript 2 (EAT-2) is an Src homology 2 domain-containing intracellular adaptor related to signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), the X-linked lymphoproliferative gene product. Both EAT-2 and SAP are expressed in natural killer (NK) cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells. SAP mediates this function by coupling SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target cells...
April 7, 2014: Journal of Experimental Medicine
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