keyword
https://read.qxmd.com/read/38479166/discovery-of-5-aminopyrido-2-3-d-pyrimidin-7-8h-one-derivatives-as-new-hematopoietic-progenitor-kinase-1-hpk1-inhibitors
#1
JOURNAL ARTICLE
Xiaorong Qiu, Rong Liu, Huan Ling, Yang Zhou, Xiaomei Ren, Fengtao Zhou, Jinwei Zhang, Weixue Huang, Zhen Wang, Ke Ding
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling. While HPK1 is considered as a promising target for cancer immunotherapy, no small-molecule HPK1 inhibitors have been approved for cancer treatment. Herein, we report the discovery of a series of new HPK1 inhibitors with a 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one scaffold. The most potent compound 9f inhibited HPK1 kinase activity with an IC50 of 0.32 nM in the time-resolved fluorescence resonance energy transfer (TR-FRET) assays, while displayed reasonable selectivity in a panel of 416 kinases...
March 5, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38114429/full-t-cell-activation-and-function-in-teleosts-require-collaboration-of-first-and-co-stimulatory-signals
#2
JOURNAL ARTICLE
Wei Liang, Kang Li, Haiyou Gao, Kunming Li, Jiansong Zhang, Qian Zhang, Xinying Jiao, Jialong Yang, Xiumei Wei
Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal. However, whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown. In the present study, we discovered that the Nile tilapia ( Oreochromis niloticus ) encodes key components of the LAT signalosome, namely, LAT, ITK, GRB2, VAV1, SLP-76, GADS, and PLC-γ1. These components are evolutionarily conserved, and CD3ε mAb-induced T-cell activation markedly increased their expression...
January 18, 2024: Zoological Research
https://read.qxmd.com/read/37536217/discovery-of-potent-and-selective-hpk1-inhibitors-based-on-the-2-4-disubstituted-pyrimidine-scaffold-with-immune-modulatory-properties-for-ameliorating-t-cell-exhaustion
#3
JOURNAL ARTICLE
Shenxin Zeng, Ming Zeng, Shuai Yuan, Liuxun He, Yuyuan Jin, Jiandong Huang, Manxuan Zhang, Menghan Yang, Youlu Pan, Zunyuan Wang, Yinqiao Chen, Xiangwei Xu, Wenhai Huang
Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50  = 1...
July 10, 2023: Bioorganic Chemistry
https://read.qxmd.com/read/37040441/shp-1-localization-to-the-activating-immune-synapse-promotes-nk-cell-tolerance-in-mhc-class-i-deficiency
#4
JOURNAL ARTICLE
Laurent Schmied, Thuy T Luu, Jonas N Søndergaard, Sophia H Hald, Stephan Meinke, Dara K Mohammad, Sunitha B Singh, Corinna Mayer, Giovanna Perinetti Casoni, Michael Chrobok, Heinrich Schlums, Giorgia Rota, Hieu M Truong, Lisa S Westerberg, Greta Guarda, Evren Alici, Arnika K Wagner, Nadir Kadri, Yenan T Bryceson, Mezida B Saeed, Petter Höglund
Natural killer (NK) cells recognize virally infected cells and tumors. NK cell function depends on balanced signaling from activating receptors, recognizing products from tumors or viruses, and inhibitory receptors (such as KIR/Ly49), which recognize major histocompatibility complex class I (MHC-I) molecules. KIR/Ly49 signaling preserves tolerance to self but also conveys reactivity toward MHC-I-low target cells in a process known as NK cell education. Here, we found that NK cell tolerance and education were determined by the subcellular localization of the tyrosine phosphatase SHP-1...
April 11, 2023: Science Signaling
https://read.qxmd.com/read/36929755/logic-gated-car-t-cells-enhance-survival-and-reduce-on-target-toxicity
#5
JOURNAL ARTICLE
(no author information available yet)
Chimeric antigen receptors (CAR) comprised of LAT and SLP-76 enable logic-gated T-cell activation.
March 17, 2023: Cancer Discovery
https://read.qxmd.com/read/36890224/co-opting-signalling-molecules-enables-logic-gated-control-of-car-t-cells
#6
JOURNAL ARTICLE
Aidan M Tousley, Maria Caterina Rotiroti, Louai Labanieh, Lea Wenting Rysavy, Won-Ju Kim, Caleb Lareau, Elena Sotillo, Evan W Weber, Skyler P Rietberg, Guillermo Nicolas Dalton, Yajie Yin, Dorota Klysz, Peng Xu, Eva L de la Serna, Alexander R Dunn, Ansuman T Satpathy, Crystal L Mackall, Robbie G Majzner
Although chimeric antigen receptor (CAR) T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumour toxicity has hampered their development for solid tumours because most target antigens are shared with normal cells1,2 . Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity3-5 ; however, a truly safe and effective logic-gated CAR has remained elusive6 . Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules...
March 2023: Nature
https://read.qxmd.com/read/36737806/correction-vacuolin%C3%A2-1-enhances-ra%C3%A2-induced-differentiation-of-human-myeloblastic-leukemia-cells-evidence-for-involvement-of-a-cd11b-fak-lyn-slp%C3%A2-76-axis-subject-to-endosomal-regulation-that-drives-late-differentiation-steps
#7
https://read.qxmd.com/read/36551835/the-functional-properties-and-physiological-roles-of-signal-transducing-adaptor-protein-2-in-the-pathogenesis-of-inflammatory-and-immune-disorders
#8
REVIEW
Jun-Ichi Kashiwakura, Kenji Oritani, Tadashi Matsuda
Adaptor molecules play a crucial role in signal transduction in immune cells. Several adaptor molecules, such as the linker for the activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76), are essential for T cell development and activation following T cell receptor (TCR) aggregation, suggesting that adaptor molecules are good therapeutic targets for T cell-mediated immune disorders, such as autoimmune diseases and allergies. Signal-transducing adaptor protein (STAP)-2 is a member of the STAP family of adaptor proteins...
November 30, 2022: Biomedicines
https://read.qxmd.com/read/36329484/vacuolin-1-enhances-ra-induced-differentiation-of-human-myeloblastic-leukemia-cells-evidence-for-involvement-of-a-cd11b-fak-lyn-slp-76-axis-subject-to-endosomal-regulation-that-drives-late-differentiation-steps
#9
JOURNAL ARTICLE
Kaiyuan Zhu, Noor Kazim, Jianbo Yue, Andrew Yen
BACKGROUND: Retinoic acid(RA), an embryonic morphogen, regulates cell differentiation. Endocytosis regulates receptor signaling that governs such RA-directed cellular processes. Vacuolin-1 is a small molecule that disrupts endocytosis, motivating interest in its effect on RA-induced differentiation/arrest. In HL-60 myeloblastic-leukemia cells, RA causes differentiation evidenced by a progression of cell-surface and functional markers, CD38, CD11b, and finally reactive oxygen species(ROS) production and G1/0 cell cycle arrest in mature cells...
November 3, 2022: Cell & Bioscience
https://read.qxmd.com/read/35780036/modulating-t-cell-activation-with-antisense-oligonucleotides-targeting-lymphocyte-cytosolic-protein-2
#10
JOURNAL ARTICLE
Vaishnavi Srinivasan Iyer, Sanjaykumar V Boddul, Anna-Karin Johnsson, Bruno Raposo, Ravi K Sharma, Yunbing Shen, Zsolt Kasza, Kah Wai Lim, Karine Chemin, Gunnar Nilsson, Vivianne Malmström, Anh Tuân Phan, Fredrik Wermeling
Dysregulated T-cell activation is a hallmark of several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). The lymphocyte cytosolic protein 2 (LCP2), also known as SLP-76, is essential for the development and activation of T cells. Despite the critical role of LCP2 in T-cell activation and the need for developing drugs that modify T-cell activation, no LCP2 inhibitors have been developed. This can be explained by the "undruggable" nature of LCP2, lacking a structure permissive to standard small molecule inhibitor modalities...
July 2022: Journal of Autoimmunity
https://read.qxmd.com/read/35471915/correction-for-bonilla-et-al-adapter-proteins-slp-76-and-blnk-both-are-expressed-by-murine-macrophages-and-are-linked-to-signaling-via-fc%C3%AE-receptors-i-and-ii-iii
#11
JOURNAL ARTICLE
(no author information available yet)
No abstract text is available yet for this article.
May 3, 2022: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/35124007/in-vitro-reconstitution-reveals-cooperative-mechanisms-of-adapter-protein-mediated-activation-of-phospholipase-c-%C3%AE-1-in-t-cells
#12
JOURNAL ARTICLE
Junya Wada, Udumbara Rathnayake, Lisa M Jenkins, Avinash Singh, Moosa Mohammadi, Ettore Appella, Paul A Randazzo, Lawrence E Samelson
Activation of T cells upon engagement of the T cell antigen receptor rapidly leads to a number of phosphorylation and plasma membrane recruitment events. For example, translocation of phospholipase-Cγ1 (PLC-γ1) to the plasma membrane and its association with the transmembrane adapter protein LAT and two other adapter proteins, Gads and SLP-76, are critical events in the early T cell activation process. We have previously characterized the formation of a tetrameric LAT-Gads-SLP-76-PLC-γ1 complex by reconstitution in vitro and have also characterized the thermodynamics of tetramer formation...
February 3, 2022: Journal of Biological Chemistry
https://read.qxmd.com/read/35075687/il-27-signaling-negatively-regulates-fc%C3%A9-ri-mediated-mast-cell-activation-and-allergic-response
#13
JOURNAL ARTICLE
Xiaopeng Wan, Yuanyuan Zhang, Huanna Tang, Mengyao Li, Tianqi Jiang, Jia He, Chunjing Bao, Junkai Wang, Yinjing Song, Peng Xiao, Yang Liu, Lihua Lai, Qingqing Wang
IL-27 is a member of the IL-12 family, exerting both anti- and pro-inflammatory activity in a cell-dependent and disease context-specific manner. Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in mast cell degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. Here, we show that the activation of mast cells is negatively regulated by IL-27 signaling. We found that mice lacking IL-27Rα (WSX-1) displayed increased sensitivity to IgE-mediated skin allergic response and chronic airway inflammation...
September 2022: Journal of Leukocyte Biology
https://read.qxmd.com/read/34844506/reciprocal-sh2-sh3-domain-contacts-between-itk-molecules-limit-t-cell-receptor-signaling-in-th2-type-cd4-t-cells
#14
JOURNAL ARTICLE
Ji-Long Chen, Jennifer Y Barr, Jonathan J Zuk, Jacob V Gorman, John D Colgan
The nonreceptor tyrosine kinase ITK is a key component of the T cell receptor (TCR) signaling pathway and is required for cytokine production by CD4+ T cells that have differentiated into Th2 cells. Structural and biochemical studies suggest that contacts between the SH2 and SH3 domains of ITK mediate intermolecular self-association, forming a structure that restrains ITK activity by interfering with interactions between ITK and other components of the TCR signaling pathway. Wild-type (WT) ITK and a panel of ITK mutants containing amino acid substitutions in the SH2 and SH3 domains were tested for self-association and for binding to the adaptor protein SLP76, a key ligand for the ITK SH2 domain...
August 2022: Immunological Investigations
https://read.qxmd.com/read/34836491/evidence-of-off-target-effects-of-bosutinib-that-promote-retinoic-acid-induced-differentiation-of-non-apl-aml-cells
#15
JOURNAL ARTICLE
Noor Kazim, Andrew Yen
In the present study, we determined the effects of the Src family kinase (SFK) inhibitor, Bosutinib, and the engineered loss of the Lyn SFK on all-trans retinoic acid-induced leukemic cell differentiation. Retinoic acid (RA) is an embryonic morphogen and dietary factor that demonstrates chemotherapeutic efficacy in inducing differentiation of a non-APL AML cell model, the HL-60 human myeloblastic (FAB-M2) leukemia cell line, via activation of a novel signalsome containing an ensemble of signaling molecules that drive differentiation...
December 2021: Cell Cycle
https://read.qxmd.com/read/34471367/distinct-proteomic-profiling-of-plasma-extracellular-vesicles-from-moderate-to-severe-atopic-dermatitis-patients
#16
JOURNAL ARTICLE
Chih-Jung Chang, Hai-Qing Wang, Jing Zhang, Ying Zou, Yi-Hua Zhang, Jia-Wen Chen, Chun-Bing Chen, Wen-Hung Chung, Chao Ji
BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disorder characterized by a T helper 2 (Th2) immune response phenotype. Extracellular vesicles (EVs) are a heterogeneous family of cell-derived membranous structures, which transport cellular components such as DNA and proteins, and are involved in multiple physiological and pathological processes. Increasing evidence has shown that EVs secretion took part in the pathogenesis of AD. However, the proteomic studies of plasma-derived EVs in AD patients have not been reported...
2021: Clinical, Cosmetic and Investigational Dermatology
https://read.qxmd.com/read/34456914/the-clinical-aspect-of-adaptor-molecules-in-t-cell-signaling-lessons-learnt-from-inborn-errors-of-immunity
#17
REVIEW
Yael Dinur-Schejter, Irina Zaidman, Hagar Mor-Shaked, Polina Stepensky
Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP-76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, have been described as the cause of human inborn errors of immunity (IEI)...
2021: Frontiers in Immunology
https://read.qxmd.com/read/34294876/tumor-derived-nkg2d-ligand-smic-reprograms-nk-cells-to-an-inflammatory-phenotype-through-cbm-signalosome-activation
#18
JOURNAL ARTICLE
Payal Dhar, Fahmin Basher, Zhe Ji, Lei Huang, Si Qin, Derek A Wainwright, Jerid Robinson, Shaye Hagler, Jing Zhou, Sean MacKay, Jennifer D Wu
Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. Here, we demonstrate that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cell to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Antibody clearing sMIC restores NK cell to a normal cytotoxic effector functional state. We discovered that sMIC selectively activates the CBM-signalosome inflammatory pathways in NK cells...
July 22, 2021: Communications Biology
https://read.qxmd.com/read/34279667/lfa-1-and-kindlin-3-enable-the-collaborative-transport-of-slp-76-microclusters-by-myosin-and-dynein-motors
#19
JOURNAL ARTICLE
Keith P Eidell, Alenka Lovy, Nicholas R Sylvain, Frank A Scangarello, Hayley I Muendlein, Michael J Ophir, Ken Nguyen, Maria-Cristina Seminario, Stephen C Bunnell
Integrin engagement within the immune synapse enhances T cell activation, but our understanding of this process is incomplete. In response to T cell receptor (TCR) ligation, SLP-76 (LCP2), ADAP (FYB1) and SKAP55 (SKAP1) are recruited into microclusters and activate integrins via the effectors talin-1 and kindlin-3 (FERMT3). We postulated that integrins influence the centripetal transport and signaling of SLP-76 microclusters via these linkages. We show that contractile myosin filaments surround and are co-transported with SLP-76 microclusters, and that TCR ligand density governs the centripetal movement of both structures...
August 15, 2021: Journal of Cell Science
https://read.qxmd.com/read/34143834/recruitment-of-phospholipase-c%C3%AE-1-to-the-non-structural-membrane-protein-pk15-of-kaposi-sarcoma-associated-herpesvirus-promotes-its-src-dependent-phosphorylation
#20
JOURNAL ARTICLE
Naira Samarina, George Ssebyatika, Tanvi Tikla, Ja-Yun Waldmann, Bizunesh Abere, Vittoria Nanna, Michelangelo Marasco, Teresa Carlomagno, Thomas Krey, Thomas F Schulz
Kaposi Sarcoma-associated herpesvirus (KSHV) causes three human malignancies, Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and the plasma cell variant of multicentric Castleman's Disease (MCD), as well as an inflammatory cytokine syndrome (KICS). Its non-structural membrane protein, pK15, is among a limited set of viral proteins expressed in KSHV-infected KS tumor cells. Following its phosphorylation by Src family tyrosine kinases, pK15 recruits phospholipase C gamma 1 (PLCγ1) to activate downstream signaling cascades such as the MEK/ERK, NFkB and PI3K pathway, and thereby contributes to the increased proliferation and migration as well as the spindle cell morphology of KSHV-infected endothelial cells...
June 2021: PLoS Pathogens
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