المؤلفون: Goodfellow, Hanna Sjölin, Frushicheva, Maria P, Ji, Qinqin, Cheng, Debra A, Kadlecek, Theresa A, Cantor, Aaron J, Kuriyan, John, Chakraborty, Arup K, Salomon, Arthur, Weiss, Arthur

المصدر: Science Signaling. 8(377)

مصطلحات موضوعية: Clinical Research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Inflammatory and immune system, Catalysis, Feedback, Physiological, Humans, Immunity, Cellular, Jurkat Cells, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Mass Spectrometry, Models, Immunological, Phosphopeptides, Phosphorylation, Proteomics, Receptors, Antigen, T-Cell, Signal Transduction, ZAP-70 Protein-Tyrosine Kinase, Biochemistry and Cell Biology

الوصف: T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells while avoiding autoimmunity. The Src family kinase Lck and the Syk family kinase ZAP-70 (ζ chain-associated protein kinase of 70 kD) are sequentially activated in response to TCR engagement and serve as critical components of the TCR signaling machinery that leads to T cell activation. We performed a mass spectrometry-based phosphoproteomic study comparing the quantitative differences in the temporal dynamics of phosphorylation in stimulated and unstimulated T cells with or without inhibition of ZAP-70 catalytic activity. The data indicated that the kinase activity of ZAP-70 stimulates negative feedback pathways that target Lck and thereby modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and ζ chain components of the TCR and of signaling molecules downstream of Lck, including ZAP-70. We developed a computational model that provides a mechanistic explanation for the experimental findings on ITAM phosphorylation in wild-type cells, ZAP-70-deficient cells, and cells with inhibited ZAP-70 catalytic activity. This model incorporated negative feedback regulation of Lck activity by the kinase activity of ZAP-70 and predicted the order in which tyrosines in the ITAMs of TCR ζ chains must be phosphorylated to be consistent with the experimental data.

الوصول الحر: https://escholarship.org/uc/item/9rz7n24sTest

المؤلفون: Sjolin-Goodfellow, Hanna, Frushicheva, Maria P., Ji, Qinqin, Cheng, Debra A., Kadlecek, Theresa A., Cantor, Aaron J., Kuriyan, John, Salomon, Arthur R., Weiss, Arthur, Chakraborty, Arup K

المساهمون: Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Department of Physics, Frushicheva, Maria P., Chakraborty, Arup K.

المصدر: PMC

الوصف: T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells while avoiding autoimmunity. The Src family kinase Lck and the Syk family kinase ZAP-70 (ζ chain–associated protein kinase of 70 kD) are sequentially activated in response to TCR engagement and serve as critical components of the TCR signaling machinery that leads to T cell activation. We performed a mass spectrometry–based phosphoproteomic study comparing the quantitative differences in the temporal dynamics of phosphorylation in stimulated and unstimulated T cells with or without inhibition of ZAP-70 catalytic activity. The data indicated that the kinase activity of ZAP-70 stimulates negative feedback pathways that target Lck and thereby modulate the phosphorylation patterns of the immunoreceptor tyrosine–based activation motifs (ITAMs) of the CD3 and ζ chain components of the TCR and of signaling molecules downstream of Lck, including ZAP-70. We developed a computational model that provides a mechanistic explanation for the experimental findings on ITAM phosphorylation in wild-type cells, ZAP-70–deficient cells, and cells with inhibited ZAP-70 catalytic activity. This model incorporated negative feedback regulation of Lck activity by the kinase activity of ZAP-70 and predicted the order in which tyrosines in the ITAMs of TCR ζ chains must be phosphorylated to be consistent with the experimental data. ; National Institutes of Health (U.S.) (Grant P01 AI91580) ; National Institutes of Health (U.S.) (Grant R01 AI083636) ; Cancer Research Institute (New York, N.Y.) (Irvington Fellowship)

وصف الملف: application/pdf

العلاقة: http://dx.doi.org/10.1126/scisignal.2005596Test; Science Signaling; http://hdl.handle.net/1721.1/101165Test; Sjolin-Goodfellow, H., M. P. Frushicheva, Q. Ji, D. A. Cheng, T. A. Kadlecek, A. J. Cantor, J. Kuriyan, A. K. Chakraborty, A. R. Salomon, and A. Weiss. “The Catalytic Activity of the Kinase ZAP-70 Mediates Basal Signaling and Negative Feedback of the T Cell Receptor Pathway.” Science Signaling 8, no. 377 (May 19, 2015): ra49–ra49.; orcid:0000-0002-7487-8858; orcid:0000-0003-1268-9602

الإتاحة: https://doi.org/10.1126/scisignal.2005596Test
http://hdl.handle.net/1721.1/101165Test

المؤلفون: Frushicheva, Maria P., Cao, Jie, Chu, Zhen T., Warshel, Arieh

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2010 Sep . 107(39), 16869-16874.

الوصول الحر: https://www.jstor.org/stable/20779878Test

المؤلفون: Avalos, Ana M., Bilate, Angelina M., Witte, Martin D., Tai, Albert K., He, Jiang, Frushicheva, Maria P., Thill, Peter Daniel, Meyer-Wentrup, Friederike, Theile, Christopher S., Chakraborty, Arup K., Zhuang, Xiaowei, Ploegh, Hidde

المساهمون: Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Department of Physics, Ragon Institute of MGH, MIT and Harvard, Whitehead Institute for Biomedical Research, Frushicheva, Maria P., Thill, Peter Daniel, Chakraborty, Arup K., Ploegh, Hidde

المصدر: Rockefeller University Press

الوصف: Valency requirements for B cell activation upon antigen encounter are poorly understood. OB1 transnuclear B cells express an IgG1 B cell receptor (BCR) specific for ovalbumin (OVA), the epitope of which can be mimicked using short synthetic peptides to allow antigen-specific engagement of the BCR. By altering length and valency of epitope-bearing synthetic peptides, we examined the properties of ligands required for optimal OB1 B cell activation. Monovalent engagement of the BCR with an epitope-bearing 17-mer synthetic peptide readily activated OB1 B cells. Dimers of the minimal peptide epitope oriented in an N to N configuration were more stimulatory than their C to C counterparts. Although shorter length correlated with less activation, a monomeric 8-mer peptide epitope behaved as a weak agonist that blocked responses to cell-bound peptide antigen, a blockade which could not be reversed by CD40 ligation. The 8-mer not only delivered a suboptimal signal, which blocked subsequent responses to OVA, anti-IgG, and anti-kappa, but also competed for binding with OVA. Our results show that fine-tuning of BCR-ligand recognition can lead to B cell nonresponsiveness, activation, or inhibition. ; National Institutes of Health (U.S.) (grant R01 AI087879) ; National Institutes of Health (U.S.) (grant R01 GM100518) ; National Institutes of Health (U.S.) (grant P01 AI091580) ; Netherlands Organization for Scientific Research

وصف الملف: application/pdf

العلاقة: http://dx.doi.org/10.1084/jem.20131603Test; Journal of Experimental Medicine; http://hdl.handle.net/1721.1/90353Test; Avalos, A. M., A. M. Bilate, M. D. Witte, A. K. Tai, J. He, M. P. Frushicheva, P. D. Thill, et al. “Monovalent Engagement of the BCR Activates Ovalbumin-Specific Transnuclear B Cells.” Journal of Experimental Medicine 211, no. 2 (February 3, 2014): 365–379.; orcid:0000-0001-6259-8800; orcid:0000-0002-7487-8858; orcid:0000-0003-1268-9602; orcid:0000-0002-1090-6071

الإتاحة: https://doi.org/10.1084/jem.20131603Test
http://hdl.handle.net/1721.1/90353Test

المؤلفون: Avalos, Ana M., Bilate, Angelina M., Witte, Martin D., Tai, Albert K., He, Jiang, Frushicheva, Maria P., Thill, Peter D., Meyer-Wentrup, Friederike, Theile, Christopher S., Chakraborty, Arup K., Zhuang, Xiaowei, Ploegh, Hidde L.

المصدر: Avalos , A M , Bilate , A M , Witte , M D , Tai , A K , He , J , Frushicheva , M P , Thill , P D , Meyer-Wentrup , F , Theile , C S , Chakraborty , A K , Zhuang , X & Ploegh , H L 2014 , ' Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells ' , Journal of Experimental Medicine , vol. 211 , no. 2 , pp. 365-379 . https://doi.org/10.1084/jem.20131603Test

مصطلحات موضوعية: OPTICAL RECONSTRUCTION MICROSCOPY, ANTIGEN RECEPTOR, T-CELLS, EXPRESSION, AFFINITY, ANTIBODY, MICE, LYMPHOCYTES, INFECTION, RESPONSES

الوصف: Valency requirements for B cell activation upon antigen encounter are poorly understood. OB1 transnuclear B cells express an IgG1 B cell receptor (BCR) specific for ovalbumin (OVA), the epitope of which can be mimicked using short synthetic peptides to allow antigen-specific engagement of the BCR. By altering length and valency of epitope-bearing synthetic peptides, we examined the properties of ligands required for optimal OB1 B cell activation. Monovalent engagement of the BCR with an epitope-bearing 17-mer synthetic peptide readily activated OB1 B cells. Dimers of the minimal peptide epitope oriented in an N to N configuration were more stimulatory than their C to C counterparts. Although shorter length correlated with less activation, a monomeric 8-mer peptide epitope behaved as a weak agonist that blocked responses to cell-bound peptide antigen, a blockade which could not be reversed by CD40 ligation. The 8-mer not only delivered a suboptimal signal, which blocked subsequent responses to OVA, anti-IgG, and anti-kappa, but also competed for binding with OVA. Our results show that fine-tuning of BCR-ligand recognition can lead to B cell nonresponsiveness, activation, or inhibition.

وصف الملف: application/pdf

العلاقة: https://research.rug.nl/en/publications/83b98406-651c-41da-933a-bffd7ad7cffcTest

الإتاحة: https://doi.org/10.1084/jem.20131603Test
https://hdl.handle.net/11370/83b98406-651c-41da-933a-bffd7ad7cffcTest
https://research.rug.nl/en/publications/83b98406-651c-41da-933a-bffd7ad7cffcTest
https://pure.rug.nl/ws/files/66299588/365.full.pdfTest

المؤلفون: Frushicheva, Maria P., Weiss, Arthur, Chakraborty, Arup K.

المصدر: Biophysical Journal ; volume 106, issue 2, page 376a-377a ; ISSN 0006-3495

مصطلحات موضوعية: Biophysics

الإتاحة: https://doi.org/10.1016/j.bpj.2013.11.2131Test
https://api.elsevier.com/content/article/PII:S0006349513033894?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0006349513033894?httpAccept=text/plainTest

المؤلفون: Frushicheva, Maria P., Warshel, Arieh

المصدر: Biophysical Journal ; volume 100, issue 3, page 219a ; ISSN 0006-3495

مصطلحات موضوعية: Biophysics

الإتاحة: https://doi.org/10.1016/j.bpj.2010.12.1407Test
https://api.elsevier.com/content/article/PII:S0006349510029103?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0006349510029103?httpAccept=text/plainTest

المؤلفون: Frushicheva, Maria P., Warshel, Arieh

المصدر: Biophysical Journal ; volume 98, issue 3, page 44a ; ISSN 0006-3495

مصطلحات موضوعية: Biophysics

الإتاحة: https://doi.org/10.1016/j.bpj.2009.12.252Test
https://api.elsevier.com/content/article/PII:S0006349509020578?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0006349509020578?httpAccept=text/plainTest

المؤلفون: Deliberato, Rodrigo Octávio, Ko, Stephanie, Komorowski, Matthieu, Armengol de La Hoz, M. A., Frushicheva, Maria P., Raffa, Jesse D., Johnson, Alistair E. W., Celi, Leo Anthony, Stone, David J.

المصدر: Critical Care Medicine ; volume 46, issue 3, page 394-400 ; ISSN 0090-3493

الوصف: Objective: Severity of illness scores rest on the assumption that patients have normal physiologic values at baseline and that patients with similar severity of illness scores have the same degree of deviation from their usual state. Prior studies have reported differences in baseline physiology, including laboratory markers, between obese and normal weight individuals, but these differences have not been analyzed in the ICU. We compared deviation from baseline of pertinent ICU laboratory test results between obese and normal weight patients, adjusted for the severity of illness. Design: Retrospective cohort study in a large ICU database. Setting: Tertiary teaching hospital. Patients: Obese and normal weight patients who had laboratory results documented between 3 days and 1 year prior to hospital admission. Interventions: None. Measurements and Main Results: Seven hundred sixty-nine normal weight patients were compared with 1,258 obese patients. After adjusting for the severity of illness score, age, comorbidity index, baseline laboratory result, and ICU type, the following deviations were found to be statistically significant: WBC 0.80 (95% CI, 0.27–1.33) × 10 9 /L; p = 0.003; log (blood urea nitrogen) 0.01 (95% CI, 0.00–0.02); p = 0.014; log (creatinine) 0.03 (95% CI, 0.02–0.05), p < 0.001; with all deviations higher in obese patients. A logistic regression analysis suggested that after adjusting for age and severity of illness at least one of these deviations had a statistically significant effect on hospital mortality ( p = 0.009). Conclusions: Among patients with the same severity of illness score, we detected clinically small but significant deviations in WBC, creatinine, and blood urea nitrogen from baseline in obese compared with normal weight patients. These small deviations are likely to be increasingly important as bigger data are analyzed in increasingly precise ways. Recognition of the extent to which all critically ill patients may deviate from their own baseline may improve the objectivity, ...

الإتاحة: https://doi.org/10.1097/ccm.0000000000002868Test
https://journals.lww.com/00003246-201803000-00007Test

المؤلفون: Sukenik, Sigalit, Frushicheva, Maria P., Waknin-Lellouche, Cecilia, Hallumi, Enas, Ifrach, Talia, Shalah, Rose, Beach, Dvora, Avidan, Reuven, Oz, Ilana, Libman, Evgeny, Aronheim, Ami, Lewinson, Oded, Yablonski, Deborah

المساهمون: Israel Science Foundation, State of Lower Saxony-Israel Collaborative Fund, Colleck Research Fund, The Russell Berrie Nanotechnology Institute, Cancer Research Institute Irvington Fellowship

المصدر: Science Signaling ; volume 10, issue 498 ; ISSN 1945-0877 1937-9145

مصطلحات موضوعية: Cell Biology, Molecular Biology, Biochemistry

الوصف: Constitutive dimerization of an adaptor molecule enables it to selectively amplify signaling by binding cooperatively to signaling complexes downstream of antigen receptors.

الإتاحة: https://doi.org/10.1126/scisignal.aal1482Test