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Tadashi Yamamoto - One of the best experts on this subject based on the ideXlab platform.
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Altered Gene Expression in the Adult Brain of FYN-Deficient Mice
Cellular and molecular neurobiology, 2004Co-Authors: June Goto, Tohru Tezuka, Takanobu Nakazawa, Nobuo Tsukamoto, Takahisa Nakamura, Rieko Ajima, Kazumasa Yokoyama, Tsutomu Ohta, Misao Ohki, Tadashi YamamotoAbstract:1. FYN, a member of Src-family tyrosine kinases, is implicated in both brain development and adult brain function. Recent studies have identified some FYN substrates, however, little is known about the transcriptional targets for FYN mediated signaling pathways. In the present study, we sought to identify targets downstream of FYN in vivo. 2. We compared genes expressed in adult hippocampi of wild-type and FYN-deficient mice using gene chips containing more than 12,000 genes. 3. The results showed that 559 transcripts were expressed differentially between these mice. Expression of 20 genes including a substantial number of myelin-associated genes was strongly repressed in FYN-deficient mice. 4. Reduced expression of these myelin-associated genes, such as MBP and MOG, in FYN-deficient mice was also confirmed by real-time PCR and northern blotting, arguing that FYN is important for function and development of oligodendrocytes. 5. Further analysis of the genes that are differently expressed in FYN-deficient mice may shed light on the molecular mechanism by which FYN regulates adult neural function.
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p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by FYN.
Biochemical and biophysical research communications, 2003Co-Authors: Sachiko Taniguchi, Tohru Tezuka, Takanobu Nakazawa, Kazumasa Yokoyama, Hui Liu, Tadashi YamamotoAbstract:FYN is a member of the Src-family protein tyrosine kinases and plays important roles in both neurons and oligodendrocytes. Here we report association of FYN with p250GAP, a RhoGAP protein that is expressed predominantly in brain. p250GAP interacts with FYN both in vitro and in vivo. p250GAP is tyrosine phosphorylated by FYN when co-expressed in HEK293T cells. This phosphorylation appears to enhance the interaction between p250GAP and FYN. Furthermore, the level of tyrosine phosphorylation of p250GAP increases upon differentiation of the oligodendrocyte cell line CG4. Given that FYN activity is up-regulated during oligodendrocyte maturation, the results argue that p250GAP is phosphorylated by FYN in oligodendrocytes. Tyrosine phosphorylation of p250GAP by FYN would regulate its RhoGAP activity, subcellular localization, or interactions with other proteins, leading to morphological and phenotypic changes of oligodendrocytes.
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psd 95 promotes FYN mediated tyrosine phosphorylation of the n methyl d aspartate receptor subunit nr2a
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Tohru Tezuka, Hisashi Umemori, Tetsu Akiyama, Shigetada Nakanishi, Tadashi YamamotoAbstract:FYN, a member of the Src-family protein-tyrosine kinase (PTK), is implicated in learning and memory that involves N-methyl-d-aspartate (NMDA) receptor function. In this study, we examined how FYN participates in synaptic plasticity by analyzing the physical and functional interaction between FYN and NMDA receptors. Results showed that tyrosine phosphorylation of NR2A, one of the NMDA receptor subunits, was reduced in FYN-mutant mice. NR2A was tyrosine-phosphorylated in 293T cells when coexpressed with FYN. Therefore, NR2A would be a substrate for FYN in vivo. Results also showed that PSD-95, which directly binds to and coclusters with NMDA receptors, promotes FYN-mediated tyrosine phosphorylation of NR2A. Different regions of PSD-95 associated with NR2A and FYN, respectively, and so PSD-95 could mediate complex formation of FYN with NR2A. PSD-95 also associated with other Src-family PTKs, Src, Yes, and Lyn. These results suggest that PSD-95 is critical for regulation of NMDA receptor activity by FYN and other Src-family PTKs, serving as a molecular scaffold for anchoring these PTKs to NR2A.
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Distinctive roles of FYN and Lyn in IgD- and IgM-mediated signaling
International immunology, 1999Co-Authors: Keisuke Horikawa, Hirofumi Nishizumi, Hisashi Umemori, Shinichi Aizawa, Kiyoshi Takatsu, Tadashi YamamotoAbstract:Src family kinases FYN and Lyn associate with the B cell antigen receptor (BCR). Accumulating data show that Lyn plays important roles in BCR-mediated signaling, while the role of FYN remains obscure. Here we dissected the role of FYN and Lyn in BCR signaling using B cells from FYN ‐/‐ , lyn ‐/‐ and FYN/lyn double-deficient (FYN ‐/‐ lyn ‐/‐ ) mice. In contrast to previous reports, FYN ‐/‐ B cells were slightly hyporeactive to both anti-IgM and anti-IgD‐dextran. Although lyn ‐/‐ B cells were hyper-reactive to anti-IgM, anti-IgD-induced proliferation was impaired in lyn ‐/‐ B cells. Most of the other phenotypes of FYN ‐/‐ lyn ‐/‐ mice were similar to that of lyn ‐/‐ mice, except that proliferative responses of B cells to various stimuli, such as BCR cross-linking and lipopolysaccharide, were significantly lower in FYN ‐/‐ lyn ‐/‐ mice than in lyn ‐/‐ mice. Finally, immune responses to thymusindependent type 2 antigen were affected in these mutant mice. These observations suggest that FYN and Lyn are involved in B cell functions, and play similar, but partly distinct, roles in BCR signaling.
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Initial events of myelination involve FYN tyrosine kinase signalling
Nature, 1994Co-Authors: Hisashi Umemori, Takeshi Yagi, Shinichi Aizawa, S. Sato, Tadashi YamamotoAbstract:MYELIN is the lipoprotein multimembrane that functions as an insulator preventing the flow of ion currents across the axonal membrane and facilitating the conduction of nerve impulses. It is synthesized by oligodendrocytes in the central nervous system at about the time of birth in mammals1. During the initial stages of myelination, several proteins are phosphorylated on tyrosine. Among these proteins, we identified FYN tyrosine kinase, one of the non–receptor–type tyrosine kinases of the Src family. Here we report that FYN tyrosine kinase is activated during the initial stages of myelination and that it is associated with the large myelin–associated glycoprotein (MAG), an adhesion molecule that has been implicated in myelinogenesis2. The FYN–large MAG association requires amino-terminal domains of FYN that include SH2 and SH3 (Src homology domains 2 and 3). Crosslinking of large MAG with antibody induces a rapid increase in the specific activity of FYN kinase. These results indicate that FYN participates in the initial events of myelination as a signalling molecule downstream of large MAG; indeed, we find that FYN–deficient mice exhibit impaired myelination.
William H. Kinsey - One of the best experts on this subject based on the ideXlab platform.
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Role of FYN Kinase in Spermatogenesis: Defects Characteristic of FYN-Null Sperm in Mice
Biology of reproduction, 2012Co-Authors: Jinping Luo, Vijayalaxmi Gupta, Brian Kern, Joseph S. Tash, Gladis Sánchez, Gustavo Blanco, William H. KinseyAbstract:FYN kinase is highly expressed in the testis and has been implicated in testis and sperm function, yet specific roles for this kinase in testis somatic and germ cells have not been defined. The purpose of the present investigation was to identify aspects of spermatogenesis, spermiation, or sperm fertilizing capacity that required FYN for normal reproductive function. Matings between FYN-null males and wild-type females resulted in normal litter sizes, despite the fact that FYN-null males exhibited reduced epididymal size and sperm count. Morphological analysis revealed a high frequency of abnormal sperm morphology among FYN-null sperm, and artificial insemination competition studies demonstrated that FYN-null sperm possessed reduced fertilizing capacity. FYN-null sperm exhibited nearly normal motility during capacitation in vitro but reduced ability to undergo the acrosome reaction and fertilize oocytes. The typical pattern of capacitation-induced protein tyrosine phosphorylation was slightly modified in FYN-null sperm, with reduced abundance of several minor phosphoproteins. These findings are consistent with a model in which FYN kinase plays an important role in proper shaping of the head and acrosome within the testis and possibly an additional role in the sperm acrosome reaction, events required for development of full fertilizing capacity in sperm.
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Role of FYN kinase in oocyte developmental potential
Reproduction fertility and development, 2010Co-Authors: Jinping Luo, Lynda K. Mcginnis, William H. KinseyAbstract:FYN kinase is highly expressed in oocytes, with inhibitor and dominant-negative studies suggesting a role in the signal transduction events during egg activation. The purpose of the present investigation was to test the hypothesis that FYN is required for calcium signalling, meiosis resumption and pronuclear congression using the FYN-knockout mouse as a model. Accelerated breeding studies revealed that FYN-null females produced smaller litter sizes at longer intervals and exhibited a rapid decline in pup production with increasing age. FYN-null females produced a similar number of oocytes, but the frequency of immature oocytes and mature oocytes with spindle chromosome abnormalities was significantly higher than in controls. Fertilised FYN-null oocytes frequently (24%) failed to undergo pronuclear congression and remained at the one-cell stage. Stimulation with gonadotropins increased the number of oocytes ovulated, but did not overcome the above defects. FYN-null oocytes overexpressed Yes kinase in an apparent effort to compensate for the loss of FYN, yet still exhibited an altered pattern of protein tyrosine phosphorylation. In summary, FYN-null female mice exhibit reduced fertility that appears to result from actin cytoskeletal defects rather than calcium signalling. These defects cause developmental arrest during oocyte maturation and pronuclear congression.
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Functions of FYN kinase in the completion of meiosis in mouse oocytes
Developmental biology, 2008Co-Authors: Lynda K. Mcginnis, William H. Kinsey, David F. AlbertiniAbstract:Oocyte maturation invokes complex signaling pathways to achieve cytoplasmic and nuclear competencies for fertilization and development. The Src-family kinases FYN, YES and SRC are expressed in mammalian oocytes but their function during oocyte maturation remains an open question. Using chemical inhibitor, siRNA knockdown, and gene deletion strategies the function of Src-family kinases was evaluated in mouse oocytes during maturation under in vivo and in vitro conditions. Suppression of Src-family as a group with SKI606 greatly reduced meiotic cell cycle progression to metaphase-II. Knockdown of FYN kinase expression after injection of FYN siRNA resulted in an approximately 50% reduction in progression to metaphase-II similar to what was observed in oocytes isolated from FYN (−/−) mice matured in vitro. Meiotic cell cycle impairment due to a FYN kinase deficiency was also evident during oocyte maturation in vivo since ovulated cumulus oocyte complexes collected from FYN (−/−) mice included immature metaphase-I oocytes (18%). Commonalities in meiotic spindle and chromosome alignment defects under these experimental conditions demonstrate a significant role for FYN kinase activity in meiotic maturation.
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Role of PTPase(s) in regulating FYN kinase at fertilization of the zebrafish egg.
Developmental biology, 2002Co-Authors: William H. KinseyAbstract:Abstract Fertilization involves the activation of Src-family protein kinases which play a role at multiple stages of the egg activation process. The objective of the present study was to determine the mechanism by which one of these kinases, the FYN kinase, is activated in response to fertilization of the zebrafish egg. Inhibitor studies demonstrated that many aspects of egg activation, including FYN activation, require phosphotyrosyl phosphatase activity. A phosphotyrosyl phosphatase was found to be tightly associated with FYN kinase and this interaction was mapped to the SH2 domain of FYN. Coimmunoprecipitation studies identified rPTPα as a phosphatase that is complexed with FYN in the egg, raising the possibility that rPTPα is part of the regulatory mechanism responsible for activating FYN at fertilization.
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Transient nuclear localization of FYN kinase during development in zebrafish.
The Anatomical record, 2000Co-Authors: Brenda J. Rongish, William H. KinseyAbstract:FYN protein tyrosine kinase is present in the unfertilized and fertilized egg, becomes activated within minutes following fertilization, and has been localized to the cortical cytoplasm and spindle apparatus of the zygote. In order to establish the expression pattern of FYN in the early embryo, we examined the distribution pattern of FYN by immunofluorescence microscopy. FYN protein is distributed evenly among cells of the cleavage stage zebrafish embryo and is concentrated in the cortical region of each cell. During blastula and gastrula stages, FYN was expressed in all cells, however a subpopulation of cells exhibited strong nuclear staining for FYN. Nuclear FYN staining was not observed after the gastrula period of development, nor in the adult zebrafish. Immunoprecipitation of FYN from isolated mid-blastula nuclei confirmed FYN was present in the nucleus. This is, to our knowledge, the first demonstration of FYN kinase, which lacks a nuclear localization signal, present in the nucleus. The transient compartmentalization of FYN in the nucleus could be important in nuclear signaling. Anat Rec 260:115‐123, 2000. © 2000 Wiley-Liss, Inc.
Takeshi Yagi - One of the best experts on this subject based on the ideXlab platform.
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FYN Tyrosine Kinase in Sertoli Cells Is Involved in Mouse Spermatogenesis
Biology of reproduction, 2002Co-Authors: Mamiko Maekawa, Takeshi Yagi, Yoshiro Toyama, Masahiro Yasuda, Shigeki YuasaAbstract:FYN is a member of the Src family of non-receptor-type tyrosine kinases and plays an important role in signal transductions regulating cell proliferation and differentiation. FYN immunoreactivity was localized in the Sertoli cells of mouse testes. Although FYN-deficient adult male mice were fertile, a significant reduction in testis weight and degenerated germ cells were observed at 3 and 4 wk of age. Electron microscopic examination revealed that FYN -/- testis has ultrastructural abnormalities in the specialized junctional structures of the Sertoli cells, the ectoplasmic specializations. Unusual vesicular structures were found in the actin filament layers of the ectoplasmic specializations of mutant mice. Immunohistochemical studies demonstrated that both FYN and actin filaments were concentrated in the areas of ectoplasmic specializations. At these sites, a high level of phosphotyrosine was also immunostained in wild-type testes, whereas phosphotyrosine immunoreactivity was reduced in FYN -/- testes. Immunoblot analyses revealed that FYN was mainly distributed within the Triton X-100-insoluble cytoskeletal fraction prepared from wild-type testes, suggesting that FYN might be associated with cytoskeletal proteins such as actin filaments. These findings suggest that FYN kinase functions at the ectoplasmic specializations of the Sertoli cells in the testes, regulating the dynamics of cytoskeletal proteins. FYN-mediated signal transduction in the Sertoli cells may affect the survival and differentiation of germ cells at a specific stage during spermatogenesis.
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Interaction of the SH2 Domain of FYN with a Cytoskeletal Protein, β-Adducin
The Journal of biological chemistry, 2001Co-Authors: Takaki Shima, Nobuaki Okumura, Takeshi Yagi, Toshifumi Takao, Yoshinori Satomi, Masato Okada, Katsuya NagaiAbstract:Abstract FYN is a Src family tyrosine kinase expressed abundantly in neurons and believed to have specific functions in the brain. To understand the function of FYN tyrosine kinase, we attempted to identify FYN Src homology 2 (SH2) domain-binding proteins from a Nonidet P-40-insoluble fraction of the mouse brain. β-Adducin, an actin filament-associated cytoskeletal protein, was isolated by two-dimensional gel electrophoresis and identified by tandem mass spectrometry. β-Adducin was tyrosine phosphorylated by coexpression with wild type but not with a kinase-negative form of FYN in COS-7 cells. Cell staining analysis showed that coexpression of β-adducin with FYN induced translocation of β-adducin from the cytoplasm to the periphery of the cells where it was colocalized with actin filaments and FYN. These findings suggest that tyrosine-phosphorylated β-adducin associates with the SH2 domain of FYN and colocalizes under plasma membranes.
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Differential effect of FYN tyrosine kinase deletion on offensive and defensive aggression.
Behavioural brain research, 2001Co-Authors: Tsuyoshi Miyakawa, Takeshi Yagi, Keizo Takao, Hiroaki NikiAbstract:Abstract FYN tyrosine kinase is highly expressed in the limbic system and mice lacking FYN tyrosine kinase showed increased fearfulness in a variety of tests for anxiety-related behaviors. To investigate the possible role of FYN tyrosine kinase in aggression, we assessed the aggressive behaviors of the mice lacking the FYN tyrosine kinase using the resident–intruder and restraint-induced target biting paradigms. The percentage of FYN-deficient mice that attacked an inanimate target in a restraint tube was higher than that of the control mice. On the contrary, in the resident–intruder paradigm, the percentage of FYN-deficient mice that attacked the intruder was lower and the FYN-deficient mice showed a longer latency to attack an intruder. These results suggest a distinct role of FYN tyrosine kinase in enhancing the offensive aggression and decreasing the defensive aggression. A possible influence of anxiety-phenotype of the FYN-deficient mice on their abnormal aggressive behavior was discussed.
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Enhanced susceptibility of audiogenic seizures in FYN-kinase deficient mice
Brain research. Molecular brain research, 1995Co-Authors: Tsuyoshi Miyakawa, Takeshi Yagi, Masahiko Taniguchi, Hiroaki Matsuura, Kyoko Tateishi, Hiroaki NikiAbstract:Abstract Mice with a mutation in FYN genes were examined for their susceptibility to acoustically primed audiogenic seizures. Homozygous mutant ( FYN z FYN z ) mice were significantly more likely to have seizures and to show the stronger seizure syndrome (clonus). These results indicate that the susceptibility of acoustically primed audiogenic seizures is enhanced in the FYN kinase deficient mice.
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Initial events of myelination involve FYN tyrosine kinase signalling
Nature, 1994Co-Authors: Hisashi Umemori, Takeshi Yagi, Shinichi Aizawa, S. Sato, Tadashi YamamotoAbstract:MYELIN is the lipoprotein multimembrane that functions as an insulator preventing the flow of ion currents across the axonal membrane and facilitating the conduction of nerve impulses. It is synthesized by oligodendrocytes in the central nervous system at about the time of birth in mammals1. During the initial stages of myelination, several proteins are phosphorylated on tyrosine. Among these proteins, we identified FYN tyrosine kinase, one of the non–receptor–type tyrosine kinases of the Src family. Here we report that FYN tyrosine kinase is activated during the initial stages of myelination and that it is associated with the large myelin–associated glycoprotein (MAG), an adhesion molecule that has been implicated in myelinogenesis2. The FYN–large MAG association requires amino-terminal domains of FYN that include SH2 and SH3 (Src homology domains 2 and 3). Crosslinking of large MAG with antibody induces a rapid increase in the specific activity of FYN kinase. These results indicate that FYN participates in the initial events of myelination as a signalling molecule downstream of large MAG; indeed, we find that FYN–deficient mice exhibit impaired myelination.
John F. Macdonald - One of the best experts on this subject based on the ideXlab platform.
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regulation of nmda receptors by the tyrosine kinase FYN
FEBS Journal, 2012Co-Authors: Catherine Trepanier, Michael F. Jackson, John F. MacdonaldAbstract:The phosphorylation and trafficking of N-methyl-d-aspartate (NMDA) receptors are tightly regulated by the Src family tyrosine kinase FYN, through dynamic interactions with various scaffolding proteins in the NMDA receptor complex. FYN acts as a point of convergence for many signaling pathways that upregulate GluN2B-containing NMDA receptors. In the following review, we focus on FYN signaling downstream of different G-protein-coupled receptors: the dopamine D1 receptor, and receptors cognate to the pituitary adenylate cyclase-activating polypeptide. The net result of activation of each of these signaling pathways is upregulation of GluN2B-containing NMDA receptors. The NMDA receptor is a major target of ethanol in the brain, and accumulating evidence suggests that FYN mediates the effects of ethanol by regulating the phosphorylation of GluN2B NMDA receptor subunits. Furthermore, FYN has been shown to regulate alcohol withdrawal and acute tolerance to ethanol through a GluN2B-dependent mechanism. In addition to its effects on NMDA receptor function, FYN also modifies the threshold for synaptic plasticity at CA1 synapses, an effect that probably contributes to the effects of FYN on spatial and contextual fear learning.
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FYN, a Potential Target for Alzheimer's Disease
Journal of Alzheimer's disease : JAD, 2011Co-Authors: Kai Yang, Jillian C. Belrose, Catherine H. Trepanier, Gang Lei, Michael F. Jackson, John F. MacdonaldAbstract:Alzheimer's disease (AD) is the most common form of dementia characterized by the presence of amyloid- (A) plaques and neurofibrillary tangles. The mechanisms leading to AD are not completely understood; however, recent evidence suggests that alterations in FYN, a Src family kinase, might contribute to AD pathogenesis. A number of studies have demon- strated that FYN is involved in synaptic plasticity, a cellular mechanism for learning and memory. In addition, FYN plays a role in the regulation of A production and mediates A-induced synaptic deficits and neurotoxicity. FYN also induces tyrosine phos- phorylation of tau. Although many studies have implicated a role for FYN in AD, the precise cellular and molecular mechanisms require further investigation. Novel insights into the role of FYN in AD may help identify alternative pharmacological approaches for the treatment of AD.
Maria G Castro - One of the best experts on this subject based on the ideXlab platform.
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erratum FYN tyrosine kinase a downstream target of receptor tyrosine kinases modulates antiglioma immune responses
Neuro-oncology, 2020Co-Authors: Andrea Comba, Patrick Dunn, Anna E Argento, Padma Kadiyala, Maria Ventosa, Priti Patel, Daniel Zamler, Felipe J Nunez, Lili Zhao, Maria G CastroAbstract:Background High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. FYN's role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion. Methods We evaluated the role of FYN using genetically engineered mouse glioma models (GEMMs). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME. Results We demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8-/- and CD4-/- immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the FYN glioma TME. Conclusions Gliomas employ FYN mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies.
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FYN tyrosine kinase a downstream target of receptor tyrosine kinases modulates anti glioma immune responses
bioRxiv, 2019Co-Authors: Andrea Comba, Patrick Dunn, Anna E Argento, Padma Kadiyala, Maria Ventosa, Priti Patel, Daniel Zamler, Felipe J Nunez, Lili Zhao, Maria G CastroAbstract:ABSTRACT Background High grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYN’s role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion. Methods We evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME. Results We demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8−/− and CD4−/− immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME. Conclusions Gliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies. Key points Inhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity. Importance of the Study FYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.
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the proto oncogene FYN inhibits the anti glioblastoma immune response
bioRxiv, 2019Co-Authors: Andrea Comba, Patrick Dunn, Anna E Argento, Padma Kadiyala, Maria Ventosa, Priti Patel, Daniel Zamler, Felipe J Nunez, Lili Zhao, Maria G CastroAbstract:In vivo genetic knockdown of the proto-oncogene FYN in immunocompetent mouse glioma models significantly extended survival by 25%-77%. GSEA analysis of DE genes revealed a highly significant enrichment of gene ontologies related to immune function such as STAT-1 regulated cell differentiation, IFN{gamma} signaling, T cell activation, and NK cytotoxicity. At the gene level, STAT1, and downstream genes IFN{gamma}, IRF1, NLRC5, CIITA, TAP1, CXCL9, CCL5, H2-Q4 and H2-DMa were upregulated in FYN-knockdown tumors. These data indicate that FYN downregulation increases expression of STAT1, a major coordinator of immune responses. These data predict that knockdown of FYN should only extend survival in immunocompetent mice. Indeed, in immune-deficient NSG mice the effect of FYN-knockdown was minimal. Our data indicate that FYN exerts its main pro-tumoral activity by downregulating the anti-glioma immune response. We propose the specific inhibition of FYN as a novel therapeutic target in gliomas.
