[ { "id": "authors:56eax-ckg39", "collection": "authors", "collection_id": "56eax-ckg39", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110411-105608478", "type": "article", "title": "Regulation of GATA-3 Expression during CD4 Lineage Differentiation", "author": [ { "family_name": "Gimferer", "given_name": "Idoia", "clpid": "Gimferer-I" }, { "family_name": "Hu", "given_name": "Taishan", "clpid": "Hu-Taishan" }, { "family_name": "Simmons", "given_name": "Amie", "clpid": "Simmons-A" }, { "family_name": "Wang", "given_name": "Chi", "clpid": "Wang-Chi" }, { "family_name": "Souabni", "given_name": "Abdallah", "clpid": "Souabni-A" }, { "family_name": "Busslinger", "given_name": "Meinrad", "clpid": "Busslinger-M" }, { "family_name": "Bender", "given_name": "Timothy P.", "clpid": "Bender-T-P" }, { "family_name": "Hernandez-Hoyos", "given_name": "Gabriela", "clpid": "Hernandez-Hoyos-G" }, { "family_name": "Alberola-Ila", "given_name": "Jos\u00e9", "clpid": "Alberola-Ila-J" } ], "abstract": "GATA-3 is necessary for the development of MHC class II-restricted CD4 T cells, and its expression is increased during positive selection of these cells. TCR signals drive this upregulation, but the signaling pathways that control this process are not well understood. Using genetic and pharmacological approaches, we show that GATA-3 upregulation during thymocyte-positive selection is the result of additive inputs from the Ras/MAPK and calcineurin pathways. This upregulation requires the presence of the transcription factor c-Myb. Furthermore, we show that TH-POK can also upregulate GATA-3 in double-positive thymocytes, suggesting the existence of a positive feedback loop that contributes to lock in the initial commitment to the CD4 lineage during differentiation.", "doi": "10.4049/jimmunol.1003505", "pmcid": "PMC3074202", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2011-04-01", "series_number": "7", "volume": "186", "issue": "7", "pages": "3892-3898" }, { "id": "authors:mw4de-qsv85", "collection": "authors", "collection_id": "mw4de-qsv85", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BARintimm06", "type": "article", "title": "Phosphatidylinositol 3-kinase improves the efficiency of positive selection", "author": [ { "family_name": "Barbee", "given_name": "Susannah D.", "clpid": "Barbee-S-D" }, { "family_name": "Alberola-Ila", "given_name": "Jos\u00e9", "clpid": "Alberola-Ila-J" } ], "abstract": "We have generated transgenic mice expressing the amino-terminal fragment of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110(ABD)) in thymocytes. Expression of P110(ABD) results in constitutive activation of PI3K and in significant increases in the numbers of mature, single-positive thymocytes. We previously reported that the increase in mature cells was in part due to a defect in thymic emigration. In this study we identify another component to this phenotype. Expression of p110(ABD) results in an enhancement of positive selection, without alterations in thymocyte lifespan or negative selection. Since PI3K can affect activation of Btk, which in turn potentiates calcium fluxes, during B cell development, our results suggest that PI3K could play a role in the regulation of Itk kinases in T cells, and that both cell types share a common signaling network to modulate calcium responses downstream of their antigen receptor.", "doi": "10.1093/intimm/dxl027", "issn": "0953-8178", "publisher": "International Immunology", "publication": "International Immunology", "publication_date": "2006-06-01", "series_number": "6", "volume": "18", "issue": "6", "pages": "921-930" }, { "id": "authors:4jztr-wwf50", "collection": "authors", "collection_id": "4jztr-wwf50", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:GREbmccb05", "type": "article", "title": "Development of ERK Activity Sensor, an in vitro, FRET-based sensor of Extracellular Regulated Kinase activity", "author": [ { "family_name": "Green", "given_name": "Harry M.", "clpid": "Green-H-M" }, { "family_name": "Alberola-Ila", "given_name": "Jose", "clpid": "Alberola-Ila-J" } ], "abstract": "Background: \nStudy of ERK activation has thus far relied on biochemical assays that are limited to the use of phospho-specific antibodies and radioactivity in vitro, and analysis of whole cell populations in vivo. As with many systems, fluorescence resonance energy transfer (FRET) can be utilized to make highly sensitive detectors of molecular activity. Here we introduce FRET-based ERK Activity Sensors, which utilize variants of Enhanced Green Fluorescent Protein fused by an ERK-specific peptide linker to detect ERK2 activity.\n \nResults: \nERK Activity Sensors display varying changes in FRET upon phosphorylation by active ERK2 in vitro depending on the composition of ERK-specific peptide linker sequences derived from known in vivo ERK targets, Ets1 and Elk1. Analysis of point mutations reveals specific residues involved in ERK binding and phosphorylation of ERK Activity Sensor 3. ERK2 also shows high in vitro specificity for these sensors over two other major MAP Kinases, p38 and pSAPK/JNK.\n\nConclusion: \nEAS's are a convenient, non-radioactive alternative to study ERK dynamics in vitro. They can be utilized to study ERK activity in real-time. This new technology can be applied to studying ERK kinetics in vitro, analysis of ERK activity in whole cell extracts, and high-throughput screening technologies.", "doi": "10.1186/1472-6769-5-1", "pmcid": "PMC1180429", "issn": "1472-6769", "publisher": "BioMed Central", "publication": "BMC Chemical Biology", "publication_date": "2005-07-05", "volume": "5", "pages": "Art. no. 1" }, { "id": "authors:rt921-trj63", "collection": "authors", "collection_id": "rt921-trj63", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170207-111452870", "type": "article", "title": "GATA-3 Expression Is Controlled by TCR Signals and Regulates CD4/CD8 Differentiation", "author": [ { "family_name": "Hern\u00e1ndez-Hoyos", "given_name": "Gabriela", "clpid": "Hern\u00e1ndez-Hoyos-G" }, { "family_name": "Anderson", "given_name": "Michele K.", "clpid": "Anderson-M-K" }, { "family_name": "Wang", "given_name": "Chi", "clpid": "Wang-Chi" }, { "family_name": "Rothenberg", "given_name": "Ellen V.", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Alberola-Ila", "given_name": "Jos\u00e9", "clpid": "Alberola-Ila-J" } ], "abstract": "GATA-3 is expressed at higher levels in CD4 than in CD8 SP thymocytes. Here we show that upregulation of GATA-3 expression in DP thymocytes is triggered by TCR stimulation, and the extent of upregulation correlates with the strength of the TCR signal. Overexpression of GATA-3 or a partial GATA-3 agonist during positive selection inhibits CD8 SP cell development but is not sufficient to divert class I-restricted T cell precursors to the CD4 lineage. Conversely, expression of the GATA-3 antagonist ROG or of a GATA-3 siRNA hairpin markedly enhances development of CD8 SP cells and reduces CD4 SP development. We propose that GATA-3 contributes to linking the TCR signal strength to the differentiation program of CD4 and CD8 thymocytes.", "doi": "10.1016/S1074-7613(03)00176-6", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "2003-07", "series_number": "1", "volume": "19", "issue": "1", "pages": "83-94" }, { "id": "authors:3eb74-vea09", "collection": "authors", "collection_id": "3eb74-vea09", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150407-074526440", "type": "article", "title": "Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade", "author": [ { "family_name": "Bain", "given_name": "Gretchen", "clpid": "Bain-G" }, { "family_name": "Cravatt", "given_name": "Celia B.", "clpid": "Cravatt-C-B" }, { "family_name": "Loomans", "given_name": "Cindy", "clpid": "Loomans-C" }, { "family_name": "Alberola-Ila", "given_name": "Jos\u00e9", "clpid": "Alberola-Ila-J" }, { "family_name": "Hedrick", "given_name": "Stephen M.", "clpid": "Hedrick-S-M" }, { "family_name": "Murre", "given_name": "Cornelis", "clpid": "Murre-C" } ], "abstract": "Activation of mitogen-activated protein kinase (MAPK) pathways leads to cellular differentiation and/or proliferation in a wide variety of cell types, including developing thymocytes. The basic helix-loop-helix (bHLH) proteins E12 and E47 and an inhibitor HLH protein, Id3, play key roles in thymocyte differentiation. We show here that E2A DNA binding is lowered in primary immature thymocytes consequent to T cell receptor (TCR)-mediated ligation. Whereas expression of E2A mRNA and protein are unaltered, Id3 transcripts are rapidly induced upon signaling from the TCR. Activation of Id3 transcription is regulated in a dose-dependent manner by the extracellular signal-regulated kinase (ERK) MAPK module. These observations directly connect the ERK MAPK cascade and HLH proteins in a linear pathway.", "doi": "10.1038/84273", "issn": "1529-2908", "publisher": "Nature Publishing Group", "publication": "Nature Immunology", "publication_date": "2001-02", "series_number": "2", "volume": "2", "issue": "2", "pages": "165-171" }, { "id": "authors:vttmv-vj066", "collection": "authors", "collection_id": "vttmv-vj066", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150406-155123000", "type": "article", "title": "Disruption of T cell signaling networks and development by Grb2 haploid insufficiency", "author": [ { "family_name": "Gong", "given_name": "Qian", "clpid": "Gong-Qian" }, { "family_name": "Cheng", "given_name": "Alec M.", "clpid": "Cheng-Alec-M" }, { "family_name": "Akk", "given_name": "Antonina M.", "clpid": "Akk-A-M" }, { "family_name": "Alberola-Ila", "given_name": "Jos\u00e9", "clpid": "Alberola-Ila-J" }, { "family_name": "Gong", "given_name": "Guoqing", "clpid": "Gong-Guoqing" }, { "family_name": "Pawson", "given_name": "Tony", "clpid": "Pawson-T" }, { "family_name": "Chan", "given_name": "Andrew C.", "clpid": "Chan-Andrew-C" } ], "abstract": "The developmental processes of positive and negative selection in the thymus shape the T cell antigen receptor (TCR) repertoire and require the integration of multiple signaling networks. These networks involve the efficient assembly of macromolecular complexes and are mediated by multimodular adaptor proteins that permit the functional integration of distinct signaling molecules. We show here that decreased expression of the adaptor protein Grb2 in Grb2 +/- mice weakens TCR-induced c-Jun N-terminal kinase (JNK) and p38, but not extracellular signal\u2212regulated kinase (ERK), activation. In turn, this selective effect decreases the ability of thymocytes to undergo negative, but not positive, selection. We also show that there are differences in the signaling thresholds of the three mitogen-activated protein kinase (MAPK) families. These differences may provide a mechanism by which quantitative differences in signal strength can alter the balance of downstream signaling pathways to induce the qualitatively distinct biological outcomes of proliferation, differentiation or apoptosis.", "doi": "10.1038/83134", "issn": "1529-2908", "publisher": "Nature Publishing Group", "publication": "Nature Immunology", "publication_date": "2001-01", "series_number": "1", "volume": "2", "issue": "1", "pages": "29-36" }, { "id": "authors:9tdxa-xyb06", "collection": "authors", "collection_id": "9tdxa-xyb06", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170209-113011357", "type": "article", "title": "Lck Activity Controls CD4/CD8 T Cell Lineage Commitment", "author": [ { "family_name": "Hern\u00e1ndez-Hoyos", "given_name": "Gabriela", "clpid": "Hern\u00e1ndez-Hoyos-G" }, { "family_name": "Sohn", "given_name": "Sue J.", "clpid": "Sohn-S-J" }, { "family_name": "Rothenberg", "given_name": "Ellen V.", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Alberola-Ila", "given_name": "Jos\u00e9", "clpid": "Alberola-Ila-J" } ], "abstract": "Thymocytes carrying MHC class I\u2013restricted TCRs differentiate into CD8 T cells, while those recognizing MHC class II become CD4 T cells. The mechanisms underlying how MHC class recognition, coreceptor expression, and effector function are coordinated are not well understood. Since the tyrosine kinase Lck binds with more affinity to CD4 than CD8, it has been proposed as a candidate to mediate this process. By using transgenic mice with altered Lck activity, we show that thymocytes carrying a class II\u2013restricted TCR develop into functional CD8 T cells when Lck activity is reduced. Conversely, thymocytes carrying a class I\u2013restricted TCR develop into functional CD4 T cells when Lck activity is increased. These results directly show that quantitative differences in the Lck signal control the CD4/CD8 lineage decision.", "doi": "10.1016/S1074-7613(00)80184-3", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "2000-03-01", "series_number": "3", "volume": "12", "issue": "3", "pages": "313-322" }, { "id": "authors:gqs1p-mfm70", "collection": "authors", "collection_id": "gqs1p-mfm70", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200330-072114315", "type": "article", "title": "Analysis of the role of MKK-4/Sek-1 in T cell development and apoptosis", "author": [ { "family_name": "Alberola-Ila", "given_name": "Jos\u00e9", "clpid": "Alberola-Ila-J" }, { "family_name": "Levin", "given_name": "Steve D.", "clpid": "Levin-S-D" }, { "family_name": "Barton", "given_name": "Greg", "clpid": "Barton-G" }, { "family_name": "Forbush", "given_name": "Katherine", "clpid": "Forbush-K" }, { "family_name": "Zon", "given_name": "Leonard I.", "clpid": "Zon-L-I" }, { "family_name": "Perlmutter", "given_name": "Roger M.", "clpid": "Perlmutter-R-M" } ], "abstract": "The stress-activated protein kinases (SAPK) are a group of dual-specificity kinases with potential roles in the control of apoptosis and proliferation. In most cells they are regulated through phosphorylation by MKK-4. We have investigated the role of MKK-4 in T cell development and function by generating transgenic animals expressing catalytically inactive MKK-4 (dMKK-4) in the thymus. Our results show that overexpression of dMKK-4 does not interfere with normal T cell development. Furthermore, expression of dMKK-4 inhibits Fas- but not phorbol ester plus ionomycin-induced activation of SAPK, suggesting that a SAPK kinase different from MKK-4 is responsible for the regulation of SAPK activation after stimulation of T cells with phorbol ester plus ionomycin. We then analyzed the effect of dMKK-4 on Fas-induced apoptosis of thymocytes. Our results show that activation of SAPK is not a necessary event in Fas-induced apoptosis of thymocytes.", "doi": "10.1093/intimm/10.8.1077", "issn": "1460-2377", "publisher": "Oxford University Press", "publication": "International Immunology", "publication_date": "1998-08", "series_number": "8", "volume": "10", "issue": "8", "pages": "1077-1082" } ]