15 results on '"Shaw, Andrey S"'
Search Results
2. SAP Signaling: A Dual Mechanism of Action
- Author
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Le Borgne, Marie and Shaw, Andrey S.
- Subjects
- *
CELLULAR signal transduction , *IMMUNITY , *ADAPTOR proteins , *AMYLOID beta-protein , *GENETIC regulation , *CELLULAR control mechanisms - Abstract
In this issue of Immunity, , and show that the adaptor protein SAP regulates both positive and negative signals through SLAM receptors to stabilize intercellular contacts. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
3. Getting Downstream without a Raft.
- Author
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Lin, Joseph and Shaw, Andrey S.
- Subjects
- *
RAFTING (Sports) , *LINEAR algebra , *LINE geometry , *MATHEMATICAL transformations , *CELL membranes , *T cells - Abstract
The role of plasma-membrane microdomains in the organization of signaling proteins has been a controversial topic in T cell signaling. In this issue of Cell, Douglass and Vale (2005) use single-molecule fluorescence to suggest that protein-protein interactions, not detergent insolubility, regulate the assembly of signaling complexes in the plasma membrane. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
4. Immature CD4+CD8+ Thymocytes Form a Multifocal Immunological Synapse with Sustained Tyrosine Phosphorylation
- Author
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Hailman, Eric, Burack, W. Richard, Shaw, Andrey S., Dustin, Michael L., and Allen, Paul M.
- Subjects
- *
SYNAPSES , *PHOSPHORYLATION , *MAJOR histocompatibility complex - Abstract
The immunological synapse formed during mature T cell activation consists of a central cluster of TCR and MHC molecules surrounded by a ring of LFA-1 and ICAM-1. We examined synapse formation in thymocytes undergoing activation in a lipid bilayer system by following the movement of fluorescent MHC and ICAM-1 molecules. Immature CD4+CD8+ thymocytes formed a decentralized synapse with multiple foci of MHC accumulation corresponding to areas of exclusion of ICAM-1. The MHC clusters and ICAM-1 holes were mobile and transient and correlated with active and sustained signaling, as shown by staining with antibodies against phosphotyrosine and activated Lck. Our findings show that signaling in immature thymocytes can result from a novel, multifocal pattern of receptor accumulation. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
5. Book review.
- Author
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Shaw, Andrey S.
- Subjects
- LYMPHOCYTE Activation (Book)
- Abstract
Reviews the book `Lymphocyte Activation,' edited by Lawrence Samuelson.
- Published
- 1995
6. Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers.
- Author
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Hu, Jiancheng, Stites, Edward?C., Yu, Haiyang, Germino, Elizabeth?A., Meharena, Hiruy?S., Stork, Philip?J.S., Kornev, Alexandr?P., Taylor, Susan?S., and Shaw, Andrey?S.
- Subjects
- *
ALLOSTERIC regulation , *RAF genes , *PROTEIN kinases , *CELL growth , *DIMERIZATION , *AUTOPHOSPHORYLATION - Abstract
Summary: Although RAF kinases are critical for controlling cell growth, their mechanism of activation is incompletely understood. Recently, dimerization was shown to be important for activation. Here we show that the dimer is functionally asymmetric with one kinase functioning as an activator to stimulate activity of the partner, receiver kinase. The activator kinase did not require kinase activity but did require N-terminal phosphorylation that functioned allosterically to induce cis-autophosphorylation of the receiver kinase. Based on modeling of the hydrophobic spine assembly, we also engineered a constitutively active mutant that was independent of Ras, dimerization, and activation-loop phosphorylation. As N-terminal phosphorylation of BRAF is constitutive, BRAF initially functions to activate CRAF. N-terminal phosphorylation of CRAF was dependent on MEK, suggesting a feedback mechanism and explaining a key difference between BRAF and CRAF. Our work illuminates distinct steps in RAF activation that function to assemble the active conformation of the RAF kinase. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
7. RAE1ε Ligand Expressed on Pancreatic Islets Recruits NKG2D Receptor-Expressing Cytotoxic T Cells Independent of T Cell Receptor Recognition
- Author
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Markiewicz, Mary A., Wise, Erica L., Buchwald, Zachary S., Pinto, Amelia K., Zafirova, Biljana, Polic, Bojan, and Shaw, Andrey S.
- Subjects
- *
LIGANDS (Biochemistry) , *ISLANDS of Langerhans , *CYTOTOXIC T cells , *T cell receptors , *LYMPHOCYTES , *LABORATORY mice , *TRETINOIN - Abstract
Summary: The mechanisms by which cytotoxic T lymphocytes (CTLs) enter and are retained in nonlymphoid tissue are not well characterized. With a transgenic mouse expressing the NKG2D ligand retinoic acid early transcript 1ε (RAE1ε) in β-islet cells of the pancreas, we found that RAE1 expression was sufficient to induce the recruitment of adoptively transferred CTLs to islets. This was dependent on NKG2D expression by the CTLs and independent of antigen recognition. Surprisingly, the recruitment of CTLs resulted in the subsequent recruitment of a large number of endogenous lymphocytes. Whereas transgenic mice did not develop diabetes, RAE1 expression was sufficient to induce insulitis in older, unmanipulated transgenic mice that was enhanced by viral infection and pancreatic inflammation. These results demonstrate that the expression of an NKG2D ligand in islets is sufficient to recruit CTLs regardless of their antigen specificity and to induce insulitis. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
8. The Balance between T Cell Receptor Signaling and Degradation at the Center of the Immunological Synapse Is Determined by Antigen Quality
- Author
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Čemerski, Sašo, Das, Jayajit, Giurisato, Emanuele, Markiewicz, Mary A., Allen, Paul M., Chakraborty, Arup K., and Shaw, Andrey S.
- Subjects
- *
CELL receptors , *T cells , *SYNAPSES , *IMMUNOLOGY , *IMMUNITY , *ANTIGENS - Abstract
Summary: The role of the center of the immunological synapse (the central supramolecular activation cluster or cSMAC) is controversial. One model suggests that the role of the cSMAC depends on antigen quality and can both enhance signaling and receptor downregulation, whereas a second model proposes that the sole function of the cSMAC is to downregulate signaling. An important distinction between the models is whether signaling occurs in the cSMAC. Here, we demonstrate that at early time points, signaling occurs outside the cSMAC, but occurs in the cSMAC at later time points. Additionally, we show that cSMAC formation enhances the stimulatory potency of weak agonists for the TCR. Combined with previous studies showing that cSMAC formation decreases the signaling by strong agonists, our data support a model proposing that signaling and receptor degradation both occur in the cSMAC and that the balance between signaling and degradation in the synapse is determined by antigen quality. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
9. The Stimulatory Potency of T Cell Antigens Is Influenced by the Formation of the Immunological Synapse
- Author
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Čemerski, Sašo, Das, Jayajit, Locasale, Jason, Arnold, Phoebe, Giurisato, Emanuele, Markiewicz, Mary A., Fremont, Daved, Allen, Paul M., Chakraborty, Arup K., and Shaw, Andrey S.
- Subjects
- *
T cell receptors , *LIGANDS (Biochemistry) , *PEPTIDES , *ANTIGENS - Abstract
Summary: T cell activation is predicated on the interaction between the T cell receptor and peptide-major histocompatibility (pMHC) ligands. The factors that determine the stimulatory potency of a pMHC molecule remain unclear. We describe results showing that a peptide exhibiting many hallmarks of a weak agonist stimulates T cells to proliferate more than the wild-type agonist ligand. An in silico approach suggested that the inability to form the central supramolecular activation cluster (cSMAC) could underlie the increased proliferation. This conclusion was supported by experiments that showed that enhancing cSMAC formation reduced stimulatory capacity of the weak peptide. Our studies highlight the fact that a complex interplay of factors determines the quality of a T cell antigen. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
10. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell...
- Author
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Dustin, Michael L., Olszowy, Michael W., Holdorf, Amy D., Li, Jun, Bromley, Shannon, Desai, Naishadh, Widder, Patricia, Rosenberger, Frederick, Van der Merwe, P. Anton, Allen, Paul M., and Shaw, Andrey S.
- Subjects
- *
CELL receptors - Abstract
Investigates the process of CD2 clustering stimulated by ligand binding and T-cell activation. Receptors required in T-cell activation; Roles of CD2 and LFA in contact formation; Clustering and segregation of CD2.
- Published
- 1998
- Full Text
- View/download PDF
11. CRAF dimerization with ARAF regulates KRAS-driven tumor growth.
- Author
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Venkatanarayan A, Liang J, Yen I, Shanahan F, Haley B, Phu L, Verschueren E, Hinkle TB, Kan D, Segal E, Long JE, Lima T, Liau NPD, Sudhamsu J, Li J, Klijn C, Piskol R, Junttila MR, Shaw AS, Merchant M, Chang MT, Kirkpatrick DS, and Malek S
- Subjects
- Animals, Carcinogenesis drug effects, Cell Line, Tumor, Humans, MAP Kinase Signaling System drug effects, Mice, Phosphorylation physiology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics, Signal Transduction drug effects, Signal Transduction physiology, ras Proteins genetics, Carcinogenesis metabolism, Dimerization, Proto-Oncogene Proteins p21(ras) metabolism
- Abstract
KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAF:ARAF dimers in KRAS mutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit., Competing Interests: Declaration of interests All authors of the paper are or were employees of Genentech/Roche during the execution of this work. A patent related to this study has been submitted: US Patent Application No. 63/108009, Recombinant Proteins for Quantification of Protein Levels., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
12. Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inflammatory Signaling.
- Author
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Goncharov T, Hedayati S, Mulvihill MM, Izrael-Tomasevic A, Zobel K, Jeet S, Fedorova AV, Eidenschenk C, deVoss J, Yu K, Shaw AS, Kirkpatrick DS, Fairbrother WJ, Deshayes K, and Vucic D
- Subjects
- Animals, Cells, Cultured, Humans, Inflammation metabolism, Inflammation pathology, Mice, Inbred C57BL, Mitogen-Activated Protein Kinases metabolism, Nod2 Signaling Adaptor Protein metabolism, Phosphorylation, Receptor-Interacting Protein Serine-Threonine Kinase 2 antagonists & inhibitors, Signal Transduction, Ubiquitin metabolism, Ubiquitination, X-Linked Inhibitor of Apoptosis Protein antagonists & inhibitors, Aminoquinolines pharmacology, Inflammation prevention & control, Nod2 Signaling Adaptor Protein antagonists & inhibitors, Protein Interaction Domains and Motifs drug effects, Receptor-Interacting Protein Serine-Threonine Kinase 2 metabolism, Sulfones pharmacology, X-Linked Inhibitor of Apoptosis Protein metabolism
- Abstract
Inflammatory responses mediated by NOD2 rely on RIP2 kinase and ubiquitin ligase XIAP for the activation of nuclear factor κB (NF-κB), mitogen-activated protein kinases (MAPKs), and cytokine production. Herein, we demonstrate that selective XIAP antagonism blocks NOD2-mediated inflammatory signaling and cytokine production by interfering with XIAP-RIP2 binding, which removes XIAP from its ubiquitination substrate RIP2. We also establish that the kinase activity of RIP2 is dispensable for NOD2 signaling. Rather, the conformation of the RIP2 kinase domain functions to regulate binding to the XIAP-BIR2 domain. Effective RIP2 kinase inhibitors block NOD2 signaling by disrupting RIP2-XIAP interaction. Finally, we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. Overall, these results reveal a critical role for the XIAP-RIP2 interaction in NOD2 inflammatory signaling and provide a molecular basis for the design of innovative therapeutic strategies based on XIAP antagonists and RIP2 kinase inhibitors., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
13. Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.
- Author
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Foster SA, Whalen DM, Özen A, Wongchenko MJ, Yin J, Yen I, Schaefer G, Mayfield JD, Chmielecki J, Stephens PJ, Albacker LA, Yan Y, Song K, Hatzivassiliou G, Eigenbrot C, Yu C, Shaw AS, Manning G, Skelton NJ, Hymowitz SG, and Malek S
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Antineoplastic Agents pharmacology, Base Pairing genetics, Conserved Sequence, Dimerization, Drug Resistance, Neoplasm genetics, Enzyme Activation genetics, ErbB Receptors metabolism, Humans, Models, Molecular, Molecular Sequence Data, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins metabolism, Neoplasms enzymology, Protein Conformation, Protein Interaction Mapping, Protein Kinase Inhibitors pharmacology, Protein Structure, Secondary, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, Sequence Alignment, Sequence Homology, Amino Acid, Structure-Activity Relationship, Genes, erbB-1, Genes, erbB-2, Mutation, Neoplasm Proteins genetics, Neoplasms genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
14. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.
- Author
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Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, Fernandez MR, Fisher K, Kortum RL, Hong EG, Jun JY, Ko HJ, Schreiner A, Volle DJ, Treece T, Swift AL, Winer M, Chen D, Wu M, Leon LR, Shaw AS, McNeish J, Kim JK, Morrison DK, Tschöp MH, and Lewis RE
- Subjects
- Adipose Tissue metabolism, Animals, COS Cells, Cells, Cultured, Chlorocebus aethiops, Fatty Acids metabolism, Glucose metabolism, Glycolysis physiology, MAP Kinase Signaling System physiology, Mice, Mice, Knockout, Obesity etiology, Obesity metabolism, Oxidation-Reduction, Oxidative Phosphorylation, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Thermogenesis physiology, AMP-Activated Protein Kinases metabolism, Energy Metabolism physiology, Insulin Resistance physiology, Protein Serine-Threonine Kinases metabolism
- Abstract
Kinase suppressors of Ras 1 and 2 (KSR1 and KSR2) function as molecular scaffolds to potently regulate the MAP kinases ERK1/2 and affect multiple cell fates. Here we show that KSR2 interacts with and modulates the activity of AMPK. KSR2 regulates AMPK-dependent glucose uptake and fatty acid oxidation in mouse embryonic fibroblasts and glycolysis in a neuronal cell line. Disruption of KSR2 in vivo impairs AMPK-regulated processes affecting fatty acid oxidation and thermogenesis to cause obesity. Despite their increased adiposity, ksr2(-/-) mice are hypophagic and hyperactive but expend less energy than wild-type mice. In addition, hyperinsulinemic-euglycemic clamp studies reveal that ksr2(-/-) mice are profoundly insulin resistant. The expression of genes mediating oxidative phosphorylation is also downregulated in the adipose tissue of ksr2(-/-) mice. These data demonstrate that ksr2(-/-) mice are highly efficient in conserving energy, revealing a novel role for KSR2 in AMPK-mediated regulation of energy metabolism.
- Published
- 2009
- Full Text
- View/download PDF
15. Immature CD4(+)CD8(+) thymocytes form a multifocal immunological synapse with sustained tyrosine phosphorylation.
- Author
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Hailman E, Burack WR, Shaw AS, Dustin ML, and Allen PM
- Subjects
- Animals, Intercellular Adhesion Molecule-1 immunology, Lipid Bilayers, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1 immunology, Mice, Mice, Transgenic, Phosphorylation, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Major Histocompatibility Complex immunology, Receptors, Antigen, T-Cell immunology, Tyrosine metabolism
- Abstract
The immunological synapse formed during mature T cell activation consists of a central cluster of TCR and MHC molecules surrounded by a ring of LFA-1 and ICAM-1. We examined synapse formation in thymocytes undergoing activation in a lipid bilayer system by following the movement of fluorescent MHC and ICAM-1 molecules. Immature CD4(+)CD8(+) thymocytes formed a decentralized synapse with multiple foci of MHC accumulation corresponding to areas of exclusion of ICAM-1. The MHC clusters and ICAM-1 holes were mobile and transient and correlated with active and sustained signaling, as shown by staining with antibodies against phosphotyrosine and activated Lck. Our findings show that signaling in immature thymocytes can result from a novel, multifocal pattern of receptor accumulation.
- Published
- 2002
- Full Text
- View/download PDF
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