{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T17:56:23Z","timestamp":1783619783692,"version":"3.55.0"},"reference-count":100,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["MT-10313"],"award-info":[{"award-number":["MT-10313"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["191117"],"award-info":[{"award-number":["191117"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Human in vitro studies of HIV Nef on TcR proximal signaling have been controversial and have not provided an integrated picture of its impact. Tyrosine (Y) phosphorylation (pY) of Lck and its substrates (CD3\u03b6, Zap-70) was investigated in vivo, in Nef-expressing transgenic (Tg) thymocytes. In Tg cells, Lck was mis-localized and activated, but the pY-CD3\u03b6 levels were unexpectedly lower, both constitutively and after anti-CD3\u03b5 Ab stimulation. Nef also favors the hyperphosphorylation of the Lck Y505 site and the accumulation of doubly phosphorylated (Y394, Y505) Lck. In contrast, after anti-CD3\u03b5+anti-CD4 Ab stimulation, Nef decreased Lck activity and Lck was deprived of its pY partners. In Nef and LckY505F Tg thymocytes, Lck had similar activity but distinct LckY505 levels, Zap-70 pY phosphorylation, and Zap-70 activity, suggesting a different mode of Lck activation. Western blot analysis of Zap-70 with pY site-specific mAb showed modest enhanced levels of Zap-70pY292 and Zap-70pY493 (the latter required for its full activation) constitutively and after anti-CD3\u03b5 Ab stimulation, consistent with elevated Tg LATpY and suggesting a semiactive kinase. In fact, phenotypes of Nef Tg mice are very similar to those of mice harboring semiactive Zap-70 mutants. After anti-CD3\u03b5+anti-CD4 stimulation, Tg Zap-70 activity and Zap-70pY493 levels were severely decreased, but Zap-70pY292 and Zap-70pY319 levels were barely affected, suggesting qualitative Lck defect. Rescue of Nef-mediated CD4+ T-cell loss with LckY505F in double (Nef \u00d7 LckY505F) Tg mice correlated with greatly enhanced levels of Zap-70pY and Zap-70 activity. Thus, Nef impacts Lck in a unique way, triggering it to mis-phosphorylate its substrates.<\/jats:p>","DOI":"10.1093\/immhor\/vlaf016","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T03:13:07Z","timestamp":1746587587000},"source":"Crossref","is-referenced-by-count":2,"title":["HIV Nef disrupts Lck signaling by inducing aberrant phosphorylation of its substrates"],"prefix":"10.1093","volume":"9","author":[{"given":"Joel","family":"Guertin","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, Clinical Research Institute of Montreal , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Chrobak","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Clinical Research Institute of Montreal , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9mence","family":"Meunier","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Clinical Research Institute of Montreal , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra M","family":"Thomson","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Clinical Research Institute of Montreal , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaher","family":"Hanna","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Clinical Research Institute of Montreal , Montreal, QC,","place":["Canada"]},{"name":"Department of Medicine, University of Montreal , Montreal, QC,","place":["Canada"]},{"name":"Division of Experimental Medicine, McGill University , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Jolicoeur","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Clinical Research Institute of Montreal , Montreal, QC,","place":["Canada"]},{"name":"Division of Experimental Medicine, McGill University , Montreal, QC,","place":["Canada"]},{"name":"Department of Microbiology\/Immunology, University of Montreal , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"2025050703570575000_vlaf016-B1","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1146\/annurev.immunol.23.021704.115737","article-title":"Molecular genetics of T cell development","volume":"23","author":"Rothenberg","year":"2005","journal-title":"Annu Rev Immunol"},{"key":"2025050703570575000_vlaf016-B2","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/0092-8674(89)90008-1","article-title":"The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain","volume":"59","author":"Shaw","year":"1989","journal-title":"Cell"},{"key":"2025050703570575000_vlaf016-B3","doi-asserted-by":"crossref","first-page":"626095","DOI":"10.3389\/fcell.2021.626095","article-title":"How the discovery of the CD4\/CD8-p56(lck) complexes changed immunology and immunotherapy","volume":"9","author":"Rudd","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2025050703570575000_vlaf016-B4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41577-018-0020-8","article-title":"Regulatory mechanisms in T cell receptor signalling","volume":"18","author":"Gaud","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"2025050703570575000_vlaf016-B5","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.aaf4736","article-title":"De novo phosphorylation and conformational opening of the tyrosine kinase Lck act in concert to initiate T cell receptor signaling","volume":"10","author":"Philipsen","year":"2017","journal-title":"Sci Signal."},{"key":"2025050703570575000_vlaf016-B6","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.tibs.2017.11.008","article-title":"TCR signaling: mechanisms of initiation and propagation","volume":"43","author":"Courtney","year":"2018","journal-title":"Trends Biochem Sci"},{"key":"2025050703570575000_vlaf016-B7","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.4049\/jimmunol.2001105","article-title":"Tyr(192) regulates lymphocyte-specific tyrosine kinase activity in T cells","volume":"207","author":"Borowicz","year":"2021","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B8","doi-asserted-by":"crossref","first-page":"7727","DOI":"10.1073\/pnas.87.19.7727","article-title":"Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion","volume":"87","author":"Schnittman","year":"1990","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B9","doi-asserted-by":"crossref","first-page":"9838","DOI":"10.1073\/pnas.88.21.9838","article-title":"Lymphoid organs function as major reservoirs for human immunodeficiency virus","volume":"88","author":"Pantaleo","year":"1991","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B10","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/j.1460-2075.1995.tb07024.x","article-title":"Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down-regulation of CD4","volume":"14","author":"Saksela","year":"1995","journal-title":"EMBO J"},{"key":"2025050703570575000_vlaf016-B11","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1128\/jvi.69.3.1842-1850.1995","article-title":"Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines","volume":"69","author":"Greenway","year":"1995","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B12","doi-asserted-by":"crossref","first-page":"6333","DOI":"10.1074\/jbc.271.11.6333","article-title":"Physical and functional interaction of Nef with Lck. HIV-1 Nef-induced T-cell signaling defects","volume":"271","author":"Collette","year":"1996","journal-title":"J Biol Chem"},{"key":"2025050703570575000_vlaf016-B13","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S1074-7613(00)80331-3","article-title":"The N-terminus of Nef from HIV-1\/SIV associates with a protein complex containing Lck and a serine kinase","volume":"6","author":"Baur","year":"1997","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B14","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1021\/bi992504j","article-title":"Affinity of Src family kinase SH3 domains for HIV Nef in vitro does not predict kinase activation by Nef in vivo","volume":"39","author":"Briggs","year":"2000","journal-title":"Biochemistry"},{"key":"2025050703570575000_vlaf016-B15","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S1074-7613(02)00307-2","article-title":"Live and let die: Nef functions beyond HIV replication","volume":"16","author":"Fackler","year":"2002","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.2217\/fvl.13.20","article-title":"HIV-1 Nef and T-cell activation: a history of contradictions","volume":"8","author":"Markle","year":"2013","journal-title":"Future Virol"},{"key":"2025050703570575000_vlaf016-B17","doi-asserted-by":"crossref","first-page":"8167","DOI":"10.1073\/pnas.96.14.8167","article-title":"HIV-1 Nef increases T cell activation in a stimulus-dependent manner","volume":"96","author":"Schrager","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B18","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1097\/00002030-200008180-00003","article-title":"HIV-Nef enhances interleukin-2 production and phosphatidylinositol 3-kinase activity in a human T cell line","volume":"14","author":"Schibeci","year":"2000","journal-title":"AIDS"},{"key":"2025050703570575000_vlaf016-B19","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1073\/pnas.97.1.394","article-title":"The Nef protein of HIV-1 associates with rafts and primes T cells for activation","volume":"97","author":"Wang","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B20","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S1074-7613(01)00158-3","article-title":"Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators","volume":"14","author":"Simmons","year":"2001","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B21","doi-asserted-by":"crossref","first-page":"6050","DOI":"10.4049\/jimmunol.175.9.6050","article-title":"Nef is physically recruited into the immunological synapse and potentiates T cell activation early after TCR engagement","volume":"175","author":"Fenard","year":"2005","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B22","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1182\/blood-2011-08-373209","article-title":"HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network-associated Lck signaling","volume":"119","author":"Pan","year":"2012","journal-title":"Blood"},{"key":"2025050703570575000_vlaf016-B23","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.4049\/jimmunol.1800372","article-title":"HIV-1 Nef hijacks Lck and Rac1 endosomal traffic to dually modulate signaling-mediated and actin cytoskeleton-mediated T cell functions","volume":"201","author":"Del R\u00edo-I\u00f1iguez","year":"2018","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B24","doi-asserted-by":"crossref","first-page":"5326","DOI":"10.1073\/pnas.88.12.5326","article-title":"Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA","volume":"88","author":"Luria","year":"1991","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B25","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.1128\/jvi.68.5.3243-3249.1994","article-title":"Human immunodeficiency virus type 1 Nef protein down-regulates transcription factors NF-kappa B and AP-1 in human T cells in vitro after T-cell receptor stimulation","volume":"68","author":"Bandres","year":"1994","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B26","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1093\/emboj\/16.4.673","article-title":"Separable functions of Nef disrupt two aspects of T cell receptor machinery: CD4 expression and CD3 signaling","volume":"16","author":"Iafrate","year":"1997","journal-title":"EMBO J"},{"key":"2025050703570575000_vlaf016-B27","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.immuni.2006.02.016","article-title":"Human immunodeficiency virus type-1 infection impairs the formation of the immunological synapse","volume":"24","author":"Thoulouze","year":"2006","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B28","doi-asserted-by":"crossref","first-page":"11528","DOI":"10.1128\/JVI.01423-09","article-title":"Inhibition of T-cell receptor-induced actin remodeling and relocalization of Lck are evolutionarily conserved activities of lentiviral Nef proteins","volume":"83","author":"Rudolph","year":"2009","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B29","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.4049\/jimmunol.1601132","article-title":"HIV-1 Nef impairs the formation of calcium membrane territories controlling the signaling nanoarchitecture at the immunological synapse","volume":"197","author":"Silva","year":"2016","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B30","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.virol.2019.02.011","article-title":"Nef-mediated inhibition of NFAT following TCR stimulation differs between HIV-1 subtypes","volume":"531","author":"Naidoo","year":"2019","journal-title":"Virology"},{"key":"2025050703570575000_vlaf016-B31","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1089\/aid.1992.8.545","article-title":"Activation pathways and human immunodeficiency virus type 1 replication are not altered in CD4+ T cells expressing the nef protein","volume":"8","author":"Schwartz","year":"1992","journal-title":"Aids Res Hum Retroviruses"},{"key":"2025050703570575000_vlaf016-B32","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1089\/aid.1994.10.523","article-title":"Role of HIV-1 Nef expression in activation pathways in CD4+ T cells","volume":"10","author":"Carreer","year":"1994","journal-title":"Aids Res Hum Retroviruses"},{"key":"2025050703570575000_vlaf016-B33","doi-asserted-by":"crossref","first-page":"3776","DOI":"10.1128\/jvi.71.5.3776-3787.1997","article-title":"Human immunodeficiency virus type 1 Nef does not alter T-cell sensitivity to antigen-specific stimulation","volume":"71","author":"Page","year":"1997","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B34","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1089\/088922204323087804","article-title":"HIV type 1 Nef increases the association of T cell receptor (TCR)-signaling molecules with T cell rafts and promotes activation-induced raft fusion","volume":"20","author":"Djordjevic","year":"2004","journal-title":"AIDS Res Hum Retroviruses"},{"key":"2025050703570575000_vlaf016-B35","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.celrep.2016.12.057","article-title":"HIV-1 activates T cell signaling independently of antigen to drive viral spread","volume":"18","author":"Len","year":"2017","journal-title":"Cell Rep"},{"key":"2025050703570575000_vlaf016-B36","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.4049\/jimmunol.154.6.2996","article-title":"HIV-1 down-regulates CD4 costimulation of TCR\/CD3-directed tyrosine phosphorylation through CD4\/p56lck dissociation","volume":"154","author":"Kanner","year":"1995","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B37","doi-asserted-by":"crossref","first-page":"19618","DOI":"10.1074\/jbc.M513802200","article-title":"The HIV-1 pathogenicity factor Nef interferes with maturation of stimulatory T-lymphocyte contacts by modulation of N-Wasp activity","volume":"281","author":"Haller","year":"2006","journal-title":"J Biol Chem"},{"key":"2025050703570575000_vlaf016-B38","doi-asserted-by":"crossref","first-page":"e1212","DOI":"10.1371\/journal.pone.0001212","article-title":"HIV-1 Nef employs two distinct mechanisms to modulate Lck subcellular localization and TCR induced actin remodeling","volume":"2","author":"Haller","year":"2007","journal-title":"PLoS ONE"},{"key":"2025050703570575000_vlaf016-B39","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/1074-7613(94)90068-X","article-title":"HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization","volume":"1","author":"Baur","year":"1994","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B40","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.virol.2010.11.018","article-title":"The HIV-1 Nef protein has a dual role in T cell receptor signaling in infected CD4+ T lymphocytes","volume":"410","author":"Neri","year":"2011","journal-title":"Virology"},{"key":"2025050703570575000_vlaf016-B41","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1046\/j.1365-4624.1997.00029.x","article-title":"HIV- I Nef severely impairs thymocyte development and peripheral T-cell function by a CD4-independent mechanism","volume":"1","author":"Pennington","year":"1997","journal-title":"Genes Funct"},{"key":"2025050703570575000_vlaf016-B42","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0092-8674(00)81748-1","article-title":"Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice","volume":"95","author":"Hanna","year":"1998","journal-title":"Cell"},{"key":"2025050703570575000_vlaf016-B43","doi-asserted-by":"crossref","first-page":"5244","DOI":"10.1128\/JVI.78.10.5244-5257.2004","article-title":"CD4 T cells from CD4C\/HIV nef transgenic mice show enhanced activation in vivo with impaired proliferation in vitro, but are dispensable for the development of a severe AIDS-like organ disease","volume":"78","author":"Weng","year":"2004","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B44","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.virol.2006.05.026","article-title":"HIV-1 transgenic rat CD4+ T cells develop decreased CD28 responsiveness and suboptimal Lck tyrosine dephosphorylation following activation","volume":"353","author":"Yadav","year":"2006","journal-title":"Virology"},{"key":"2025050703570575000_vlaf016-B45","doi-asserted-by":"crossref","first-page":"4923","DOI":"10.1002\/j.1460-2075.1993.tb06186.x","article-title":"CD4 cell surface downregulation in HIV-1 Nef transgenic mice is a consequence of intracellular sequestration","volume":"12","author":"Brady","year":"1993","journal-title":"EMBO J"},{"key":"2025050703570575000_vlaf016-B46","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/j.1460-2075.1993.tb05704.x","article-title":"Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene","volume":"12","author":"Skowronski","year":"1993","journal-title":"EMBO J"},{"key":"2025050703570575000_vlaf016-B47","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.4049\/jimmunol.1001064","article-title":"HIV-1 Nef disrupts maturation of CD4+ T cells through CD4\/Lck modulation","volume":"185","author":"Chrobak","year":"2010","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B48","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1074-7613(01)00177-7","article-title":"The AIDS disease of CD4C\/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-\u03b3 and IL-6","volume":"15","author":"Poudrier","year":"2001","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B49","doi-asserted-by":"crossref","first-page":"6377","DOI":"10.1128\/JVI.79.10.6377-6391.2005","article-title":"The Nef-mediated AIDS-like disease of CD4C\/HIV transgenic mice is associated with increased Fas\/FasL expression on T cells and T cell death, but is not prevented in Fas, FasL, TNFR-1 and ICE deficient nor in Bcl2-expressing transgenic mice","volume":"79","author":"Priceputu","year":"2005","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B50","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.4049\/jimmunol.166.4.2209","article-title":"Activated p56lck directs maturation of both CD4 and CD8 single-positive thymocytes","volume":"166","author":"Sohn","year":"2001","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B51","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/350508a0","article-title":"Serine phosphorylation-independent downregulation of cell-surface CD4 by nef","volume":"350","author":"Garcia","year":"1991","journal-title":"Nature"},{"key":"2025050703570575000_vlaf016-B52","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.immuni.2010.05.011","article-title":"Constitutively active Lck kinase in T cells drives antigen receptor signal transduction","volume":"32","author":"Nika","year":"2010","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B53","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1084\/jem.179.4.1163","article-title":"p56lck interacts via its src homology 2 domain with the ZAP-70 kinase","volume":"179","author":"Duplay","year":"1994","journal-title":"J Exp Med"},{"key":"2025050703570575000_vlaf016-B54","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1073\/pnas.062055999","article-title":"Negative regulation of Lck by Cbl ubiquitin ligase","volume":"99","author":"Rao","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B55","first-page":"E5891","article-title":"Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling","volume":"114","author":"Li","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B56","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1084\/jem.183.1.301","article-title":"Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes","volume":"183","author":"Fournel","year":"1996","journal-title":"J Exp Med"},{"key":"2025050703570575000_vlaf016-B57","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.virol.2005.03.021","article-title":"Nef enhances c-Cbl phosphorylation in HIV-infected CD4+ T lymphocytes","volume":"336","author":"Yang","year":"2005","journal-title":"Virology"},{"key":"2025050703570575000_vlaf016-B58","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1002\/eji.200737837","article-title":"Reduced Cbl phosphorylation and degradation of the zeta-chain of the T-cell receptor\/CD3 complex in T cells with low Lck levels","volume":"38","author":"Methi","year":"2008","journal-title":"Eur. J. Immunol"},{"key":"2025050703570575000_vlaf016-B59","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1042\/BJ20050892","article-title":"c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses","volume":"391","author":"Thien","year":"2005","journal-title":"Biochem J"},{"key":"2025050703570575000_vlaf016-B60","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1084\/jem.183.3.1053","article-title":"Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes","volume":"183","author":"van Oers","year":"1996","journal-title":"J Exp Med"},{"key":"2025050703570575000_vlaf016-B61","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1002\/j.1460-2075.1995.tb07247.x","article-title":"Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function","volume":"14","author":"Chan","year":"1995","journal-title":"EMBO J"},{"key":"2025050703570575000_vlaf016-B62","doi-asserted-by":"crossref","first-page":"5026","DOI":"10.1128\/MCB.16.9.5026","article-title":"Distinct tyrosine phosphorylation sites in ZAP-70 mediate activation and negative regulation of antigen receptor function","volume":"16","author":"Kong","year":"1996","journal-title":"Mol Cell Biol"},{"key":"2025050703570575000_vlaf016-B63","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1084\/jem.194.4.491","article-title":"T cell development and T cell responses in mice with mutations affecting tyrosines 292 or 315 of the ZAP-70 protein tyrosine kinase","volume":"194","author":"Magnan","year":"2001","journal-title":"J Exp Med"},{"key":"2025050703570575000_vlaf016-B64","doi-asserted-by":"crossref","first-page":"14229","DOI":"10.1074\/jbc.274.20.14229","article-title":"Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck","volume":"274","author":"Pelosi","year":"1999","journal-title":"J Biol Chem"},{"key":"2025050703570575000_vlaf016-B65","doi-asserted-by":"crossref","first-page":"6285","DOI":"10.1074\/jbc.274.10.6285","article-title":"Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling","volume":"274","author":"Di Bartolo","year":"1999","journal-title":"J Biol Chem"},{"key":"2025050703570575000_vlaf016-B66","doi-asserted-by":"crossref","first-page":"18730","DOI":"10.1074\/jbc.270.32.18730","article-title":"Activating and inhibitory mutations in adjacent tyrosines in the kinase domain of ZAP-70","volume":"270","author":"Wange","year":"1995","journal-title":"J Biol Chem"},{"key":"2025050703570575000_vlaf016-B67","doi-asserted-by":"crossref","first-page":"4924","DOI":"10.1128\/MCB.25.12.4924-4933.2005","article-title":"Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases","volume":"25","author":"Brdicka","year":"2005","journal-title":"Mol Cell Biol"},{"key":"2025050703570575000_vlaf016-B68","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.chom.2007.03.004","article-title":"HIV-1 Nef assembles a Src family kinase-ZAP-70\/Syk-PI3K cascade to downregulate cell-surface MHC-I","volume":"1","author":"Hung","year":"2007","journal-title":"Cell Host Microbe"},{"key":"2025050703570575000_vlaf016-B69","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1128\/MCB.00165-16","article-title":"Phosphorylation of a tyrosine residue on Zap70 by Lck and its subsequent binding via an SH2 domain may be a key gatekeeper of T cell receptor signaling in vivo","volume":"36","author":"Thill","year":"2016","journal-title":"Mol Cell Biol"},{"key":"2025050703570575000_vlaf016-B70","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1128\/jvi.68.5.3092-3101.1994","article-title":"The cytoplasmic domain of CD4 is sufficient for its down-regulation from the cell surface by human immunodeficiency virus type 1 Nef","volume":"68","author":"Anderson","year":"1994","journal-title":"J.Virol"},{"key":"2025050703570575000_vlaf016-B71","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1073\/pnas.92.2.349","article-title":"Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail","volume":"92","author":"Salghetti","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B72","doi-asserted-by":"crossref","first-page":"15809","DOI":"10.1073\/pnas.1913334117","article-title":"Lck bound to coreceptor is less active than free Lck","volume":"117","author":"Wei","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B73","doi-asserted-by":"crossref","first-page":"7918","DOI":"10.1038\/sj.onc.1208081","article-title":"Structure and regulation of Src family kinases","volume":"23","author":"Boggon","year":"2004","journal-title":"Oncogene"},{"key":"2025050703570575000_vlaf016-B74","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/385650a0","article-title":"Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement","volume":"385","author":"Moarefi","year":"1997","journal-title":"Nature"},{"key":"2025050703570575000_vlaf016-B75","first-page":"365","article-title":"SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo","volume":"9","author":"Lerner","year":"2002","journal-title":"Nat Struct Biol"},{"key":"2025050703570575000_vlaf016-B76","doi-asserted-by":"crossref","first-page":"27029","DOI":"10.1074\/jbc.M601128200","article-title":"HIV-1 Nef selectively activates Src family kinases Hck, Lyn, and c-Src through direct SH3 domain interaction","volume":"281","author":"Trible","year":"2006","journal-title":"J Biol. Chem"},{"key":"2025050703570575000_vlaf016-B77","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1002\/eji.200636973","article-title":"Hypophosphorylated TCR\/CD3zeta signals through a Grb2-SOS1-Ras pathway in Lck knockdown cells","volume":"37","author":"Methi","year":"2007","journal-title":"Eur J Immunol"},{"key":"2025050703570575000_vlaf016-B78","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.immuni.2005.11.003","article-title":"Nef-mediated lipid raft exclusion of UbcH7 inhibits Cbl activity in T cells to positively regulate signaling","volume":"23","author":"Simmons","year":"2005","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B79","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1084\/jem.20161575","article-title":"Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness","volume":"214","author":"Hsu","year":"2017","journal-title":"J Exp Med"},{"key":"2025050703570575000_vlaf016-B80","doi-asserted-by":"crossref","first-page":"20699","DOI":"10.1073\/pnas.0911512106","article-title":"Stability of an autoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response","volume":"106","author":"Deindl","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B81","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.4049\/jimmunol.1801159","article-title":"Strain-specific manifestation of lupus-like systemic autoimmunity caused by Zap70 mutation","volume":"202","author":"Matsuo","year":"2019","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B82","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/imr.13058","article-title":"ZAP70, too little, too much can lead to autoimmunity","volume":"307","author":"Ashouri","year":"2022","journal-title":"Immunol Rev"},{"key":"2025050703570575000_vlaf016-B83","doi-asserted-by":"crossref","first-page":"4677","DOI":"10.1128\/JVI.02691-06","article-title":"Primary human immunodeficiency virus type 1 nef alleles show major differences in pathogenicity in transgenic mice","volume":"81","author":"Priceputu","year":"2007","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B84","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.4049\/jimmunol.1203272","article-title":"HIV Nef expression favors the relative preservation of CD4+ T regulatory cells that retain some important suppressive functions","volume":"192","author":"Chrobak","year":"2014","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B85","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0002-9440(10)64184-3","article-title":"Cardiac disease in transgenic mice expressing human immunodeficiency virus-1 Nef in cells of the immune system","volume":"161","author":"Kay","year":"2002","journal-title":"Am J Pathol"},{"key":"2025050703570575000_vlaf016-B86","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.ajpath.2023.02.006","article-title":"NEF-induced HIV-associated nephropathy through HCK\/LYN tyrosine kinases","volume":"193","author":"Hu","year":"2023","journal-title":"Am J Pathol"},{"key":"2025050703570575000_vlaf016-B87","doi-asserted-by":"crossref","first-page":"e0047121","DOI":"10.1128\/JVI.00471-21","article-title":"HIV-1 Nef induces Hck\/Lyn-dependent expansion of myeloid-derived suppressor cells associated with elevated interleukin-17\/G-CSF levels","volume":"95","author":"Priceputu","year":"2021","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B88","doi-asserted-by":"crossref","first-page":"11830","DOI":"10.1128\/JVI.01466-09","article-title":"Adult AIDS-like disease in a novel inducible human immunodeficiency virus type 1 Nef transgenic mouse model: CD4+ T-cell activation is Nef dependent and can occur in the absence of lymphophenia","volume":"83","author":"Rahim","year":"2009","journal-title":"J Virol"},{"key":"2025050703570575000_vlaf016-B89","doi-asserted-by":"crossref","first-page":"6940","DOI":"10.1074\/jbc.M512710200","article-title":"Activation of p21-activated kinase 2 and its association with Nef are conserved in murine cells but are not sufficient to induce an AIDS-like disease in CD4C\/HIV transgenic mice","volume":"281","author":"Vincent","year":"2006","journal-title":"J Biol Chem"},{"key":"2025050703570575000_vlaf016-B90","doi-asserted-by":"crossref","first-page":"7324","DOI":"10.4049\/jimmunol.172.12.7324","article-title":"A novel role for p21-activated protein kinase 2 in T cell activation","volume":"172","author":"Chu","year":"2004","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B91","doi-asserted-by":"crossref","first-page":"369","DOI":"10.4049\/jimmunol.141.2.369","article-title":"Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation","volume":"141","author":"Yokoyama","year":"1988","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B92","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/373444a0","article-title":"Fas(CD95)\/FasL interactions required for programmed cell death after T-cell activation","volume":"373","author":"Ju","year":"1995","journal-title":"Nature"},{"key":"2025050703570575000_vlaf016-B93","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/357161a0","article-title":"Profound block in thymocyte development in mice lacking p56lck","volume":"357","author":"Molina","year":"1992","journal-title":"Nature"},{"key":"2025050703570575000_vlaf016-B94","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1084\/jem.173.6.1421","article-title":"Delayed thymocyte development induced by augmented expression of p56lck","volume":"173","author":"Abraham","year":"1991","journal-title":"J Exp Med"},{"key":"2025050703570575000_vlaf016-B95","doi-asserted-by":"crossref","first-page":"7133","DOI":"10.4049\/jimmunol.162.12.7133","article-title":"Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes","volume":"162","author":"Thien","year":"1999","journal-title":"J Immunol"},{"key":"2025050703570575000_vlaf016-B96","doi-asserted-by":"crossref","first-page":"15547","DOI":"10.1073\/pnas.95.26.15547","article-title":"Altered thymic positive selection and intracellular signals in Cbl-deficient mice","volume":"95","author":"Naramura","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025050703570575000_vlaf016-B97","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/376435a0","article-title":"Essential role for ZAP-70 in both positive and negative selection of thymocytes","volume":"376","author":"Negishi","year":"1995","journal-title":"Nature"},{"key":"2025050703570575000_vlaf016-B98","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/S1074-7613(00)80442-2","article-title":"A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development","volume":"6","author":"Wiest","year":"1997","journal-title":"Immunity"},{"key":"2025050703570575000_vlaf016-B99","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nsmb.2762","article-title":"In vitro membrane reconstitution of the T-cell receptor proximal signaling network","volume":"21","author":"Hui","year":"2014","journal-title":"Nat Struct Mol Biol"},{"key":"2025050703570575000_vlaf016-B100","doi-asserted-by":"crossref","first-page":"e20211295","DOI":"10.1084\/jem.20211295","article-title":"Systems-level conservation of the proximal TCR signaling network of mice and humans","volume":"219","author":"Nicolas","year":"2022","journal-title":"J Exp Med"}],"container-title":["ImmunoHorizons"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/9\/6\/vlaf016\/63071699\/vlaf016.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/9\/6\/vlaf016\/63071699\/vlaf016.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T07:57:25Z","timestamp":1746604645000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article\/doi\/10.1093\/immhor\/vlaf016\/8126102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,26]]},"references-count":100,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,4,26]]}},"URL":"https:\/\/doi.org\/10.1093\/immhor\/vlaf016","relation":{},"ISSN":["2573-7732"],"issn-type":[{"value":"2573-7732","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,4,26]]},"article-number":"vlaf016"}}