Figure S3 from Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
Nathan SinghYong Gu LeeOlga ShestovaPranali RavikumarKatharina E. HayerSeok Jae HongXueqing Maggie LuRaymone PajarilloSangya AgarwalShunichiro KuramitsuElena J. OrlandoKaren Thudium MuellerCharly R. GoodShelley L. BergerOphir ShalemMatthew D. WeitzmanNoelle V. FreyShannon L. MaudeStephan A. GruppCarl H. JuneSaar GillMarco Ruella
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<p>Persistent exposure to WT leukemia causes progressive CART19 dysfunction.</p>Topics:
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During efferocytosis, phagocytic cells recognize dying cells by receptors binding to ligands specifically exposed on apoptotic cells. Multiple phagocytic receptors and some of their signaling pathways have been identified. However, the downstream pathways of tethering receptors that secure apoptotic cells remain elusive. It is generally assumed that tethering receptors induce signaling to mediate engulfment via interacting with co-receptors or other engulfment receptors located nearby. However, it is poorly understood whether co-receptors for tethering receptors exist during efferocytosis, and, if they do, whether they are indispensable for this process. Here, we address this issue using glycophosphatidylinositol (GPI)-anchored annexin A5 (Anxa5-GPI), an artificial tethering receptor without a putative co-receptor. Phagocytes expressing Anxa5-GPI exhibited enhanced binding of apoptotic cells, resulting in promoted ingestion of apoptotic cells in a phosphatidylserine-dependent manner. Anxa5-GPI-induced phagocytosis of apoptotic cells relied on the known cytoskeletal engulfment machinery but partially depended on the Elmo-Dock-Rac module or the integrin pathway. In addition, Anxa5-GPI-mediated efferocytosis provoked anti-inflammatory responses. Taken together, our work suggests that co-receptors are dispensable for tethering receptor-induced efferocytosis and that tethering receptors mediate the engulfment of apoptotic cells through multiple engulfment signaling pathways.
efferocytosis
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Abstract Binding of a growth factor (GF) to its specific receptor on the cell surface causes the initiation of a signal transduction cascade which eventually results in mitosis. GF:receptor complexes are removed from the cell surface via receptor‐mediated endocytosis, a process which involves clathrin‐coated pits. After internalization into the endosomal compartment, a significant pool of GFs and GF receptors escape recycling to the cell surface and are sorted to the degradation pathway. The ligandinduced internalization and lysosomal degradation of GF receptors result in the dramatic loss of surface receptors, a phenomenon termed receptor down‐regulation. In this review, we discuss relevant biochemical, morphological and kinetic studies of the mechanism of GF endocytosis, and the possible role of this process in mitogenic signaling by growth factor receptors.
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Receptor expression
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ABSTRACT Banded leaf and sheath blight (BLSB) caused by Rhizoctonia solani Kühn in maize ( Zea mays L.) is an important disease in China as well as South and Southeast Asia. The identification of quantitative trait loci (QTL) for resistance to this disease would facilitate the development of disease resistant maize hybrids. A mapping population consisting of 229 F 2 individuals derived from the cross of inbreds R15 (resistant) and 478 (susceptible) was used in this study. A genetic linkage map was constructed containing 146 single sequence repeat (SSR) markers, which covered 1666 cM of the maize genome, with an average distance of 11.4 cM. All F 2:4 population individual plants were artificially inoculated by anastomosis groups AG1‐IA of R. solani at two locations for disease evaluations. Composite interval mapping (CIM) identified 11 QTL for resistance to BLSB located on chromosomes 1, 2, 3, 4, 5, 6, and 10, but only four QTL located on chromosomes 2, 6, and 10, were identified across both locations. The range of phenotypic variation explained by the QTL was 3.72 to 10.35%. The information gained from mapping resistance can be used in a marker‐assisted selection (MAS) program for the development of BLSB resistant germplasm.
Germ plasm
Sheath blight
Genetic linkage
Association mapping
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Journal Article Differences Among Medicago Species in Resistance to Oviposition by the Alfalfa Weevil Get access W. V. Campbell, W. V. Campbell North Carolina State of the University of North Carolina at Raleigh Search for other works by this author on: Oxford Academic PubMed Google Scholar J. W. Dudley J. W. Dudley North Carolina State of the University of North Carolina at Raleigh Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Economic Entomology, Volume 58, Issue 2, 1 April 1965, Pages 245–248, https://doi.org/10.1093/jee/58.2.245 Published: 01 April 1965 Article history Received: 29 June 1964 Accepted: 03 September 1964 Published: 01 April 1965
Entomology
Medicago
South carolina
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Natural killer (NK) cells play a vital role in the defense against viral infections and tumor development. NK cell function is primarily regulated by the sum of signals from a broad array of activation and inhibitory receptors. Key to generating the input level of either activating or inhibitory signals is the maintenance of receptor expression levels on the cell surface. Although the mechanisms of endocytosis and trafficking for some cell surface receptors, such as transferrin receptor and certain immune receptors, are very well known, that is not the situation for receptors expressed by NK cells. Recent studies have uncovered that endocytosis and trafficking routes characteristic for specific activation and inhibitory receptors can regulate the functional responses of NK cells. In this review, we summarize the current knowledge of receptor endocytosis and trafficking, and integrate this with our current understanding of NK cell receptor trafficking.
Immune receptor
Cell surface receptor
Transferrin receptor
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The functional expression of P2X receptors at the plasma membrane is dependent on their trafficking along secretory and endocytic pathways. There are seven P2X receptor subunits, and these differ in their subcellular distributions because they have very different trafficking properties. Some are retained within the endoplasmic reticulum (ER), while others are predominantly at the cell surface or within endosomes and lysosomes. Changes in recruitment of receptors to and from the plasma membrane provides a way of rapidly up- or down-regulating the cellular response to ATP. An additional layer of regulation is the targeting of these receptors within the membranes of each compartment, which affects their stability, function and the nature of the effector proteins with which they form signaling complexes. The trafficking and targeting of P2X receptors is regulated by their interactions with other proteins and with lipids and we can expect this to vary in a cell-type specific manner, giving rise to differences in receptor activity and function.
Cell surface receptor
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Although most solid tumors contain inactivating mutations of the p53 tumor suppressor, hematological malignancies do not contain frequent alterations in the p53 gene (<20%). How these tumors arise in the presence of a super tumor suppressor like p53 remains to be elucidated. Given the number of downstream effectors of p53, it is likely that critical targets of p53 are inactivated in leukemia, bypassing the requirement for p53 gene mutations in these tumors. This review describes new biochemical and transcriptional activities of p53 as well as the status of p53 in acute myelogenous leukemia and chronic myelogenous leukemia.
Chronic myelogenous leukemia
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