GRB2 dimerization mediated by SH2 domain-swapping is critical for T cell signaling and cytokine production

Sandouk, Aline; Xu, Zhen; Baruah, Sankar; Tremblay, Mikaela; Hopkins, Jesse B.; Chakravarthy, Srinivas; Gakhar, Lokesh; Schnicker, Nicholas J.; Houtman, Jon C. D.

doi:10.1038/s41598-023-30562-7

GRB2 dimerization mediated by SH2 domain-swapping is critical for T cell signaling and cytokine production

Journal Article · Thu Mar 02 00:00:00 EST 2023 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-023-30562-7· OSTI ID:2423446

Sandouk, Aline ^[1]; Xu, Zhen ^[1]; Baruah, Sankar ^[1]; Tremblay, Mikaela ^[1]; Hopkins, Jesse B. ^[2]; Chakravarthy, Srinivas ^[2]; Gakhar, Lokesh ^[1]; Schnicker, Nicholas J. ^[1]; Houtman, Jon C. D. ^[1]

Univ. of Iowa, Iowa City, IA (United States)
Argonne National Laboratory (ANL), Argonne, IL (United States)

GRB2 is an adaptor protein required for facilitating cytoplasmic signaling complexes from a wide array of binding partners. GRB2 has been reported to exist in either a monomeric or dimeric state in crystal and solution. GRB2 dimers are formed by the exchange of protein segments between domains, otherwise known as “domain-swapping”. Swapping has been described between SH2 and C-terminal SH3 domains in the full-length structure of GRB2 (SH2/C–SH3 domain-swapped dimer), as well as between α-helixes in isolated GRB2 SH2 domains (SH2/SH2 domain-swapped dimer). Interestingly, SH2/SH2 domain-swapping has not been observed within the full-length protein, nor have the functional influences of this novel oligomeric conformation been explored. We herein generated a model of full-length GRB2 dimer with an SH2/SH2 domain-swapped conformation supported by in-line SEC–MALS–SAXS analyses. This conformation is consistent with the previously reported truncated GRB2 SH2/SH2 domain-swapped dimer but different from the previously reported, full-length SH2/C-terminal SH3 (C–SH3) domain-swapped dimer. Our model is also validated by several novel full-length GRB2 mutants that favor either a monomeric or a dimeric state through mutations within the SH2 domain that abrogate or promote SH2/SH2 domain-swapping. GRB2 knockdown and re-expression of selected monomeric and dimeric mutants in a T cell lymphoma cell line led to notable defects in clustering of the adaptor protein LAT and IL-2 release in response to TCR stimulation. These results mirrored similarly-impaired IL-2 release in GRB2-deficient cells. These studies show that a novel dimeric GRB2 conformation with domain-swapping between SH2 domains and monomer/dimer transitions are critical for GRB2 to facilitate early signaling complexes in human T cells.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423446

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 13; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (110)

Purification, stabilization, and crystallization of a modular protein: Grb2 Guilloteau, J. P.; Fromage, N.; Ries-Kautt, M. Proteins: Structure, Function, and Bioinformatics, Vol. 25, Issue 1 https://doi.org/10.1002/(SICI)1097-0134(199605)25:1<112::AID-PROT9>3.0.CO;2-L	journal	May 1996
UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Structural insights into the intertwined dimer of fyn SH2 Huculeci, Radu; Garcia‐Pino, Abel; Buts, Lieven Protein Science, Vol. 24, Issue 12 https://doi.org/10.1002/pro.2806	journal	October 2015
Structural and biophysical investigation of the interaction of a mutant Grb2 SH2 domain (W121G) with its cognate phosphopeptide Papaioannou, Danai; Geibel, Sebastian; Kunze, Micha B. A. Protein Science, Vol. 25, Issue 3 https://doi.org/10.1002/pro.2856	journal	December 2015
SASBDB: Towards an automatically curated and validated repository for biological scattering data Kikhney, Alexey G.; Borges, Clemente R.; Molodenskiy, Dmitry S. Protein Science, Vol. 29, Issue 1 https://doi.org/10.1002/pro.3731	journal	October 2019
The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation: Adaptor protein LAT as an integration node Bartelt, Rebekah R.; Houtman, Jon C. D. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol. 5, Issue 1 https://doi.org/10.1002/wsbm.1194	journal	November 2012
Structural basis for the high affinity of amino-aromatic SH2 phosphopeptide ligands Rahuel, Joseph; Garcı́a-Echeverrı́a, Carlos; Furet, Pascal Journal of Molecular Biology, Vol. 279, Issue 4 https://doi.org/10.1006/jmbi.1998.1790	journal	June 1998
Solution structure of Grb2 reveals extensive flexibility necessary for target recognition11Edited by P. E. Wright Yuzawa, Satoru; Yokochi, Masashi; Hatanaka, Hideki Journal of Molecular Biology, Vol. 306, Issue 3 https://doi.org/10.1006/jmbi.2000.4396	journal	February 2001
Crystal structures of the SH2 domain of grb2: highlight on the binding of a new high-affinity inhibitor Nioche, Pierre; Liu, Wang-Qing; Broutin, Isabelle Journal of Molecular Biology, Vol. 315, Issue 5 https://doi.org/10.1006/jmbi.2001.5299	journal	February 2002
Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor Ogura, Kenji; Shiga, Takanori; Yokochi, Masashi Journal of Biomolecular NMR, Vol. 42, Issue 3 https://doi.org/10.1007/s10858-008-9272-0	journal	October 2008
Exploring the Roles of Proline in Three-Dimensional Domain Swapping from Structure Analysis and Molecular Dynamics Simulations Huang, Yongqi; Gao, Meng; Su, Zhengding The Protein Journal, Vol. 37, Issue 1 https://doi.org/10.1007/s10930-017-9747-5	journal	November 2017
The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling Lowenstein, E. J.; Daly, R. J.; Batzer, A. G. Cell, Vol. 70, Issue 3 https://doi.org/10.1016/0092-8674(92)90167-B	journal	August 1992
Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor Buday, László; Downward, Julian Cell, Vol. 73, Issue 3 https://doi.org/10.1016/0092-8674(93)90146-H	journal	May 1993
SH2 domains recognize specific phosphopeptide sequences Zhou, S. Cell, Vol. 72, Issue 5 https://doi.org/10.1016/0092-8674(93)90404-E	journal	March 1993
The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor. Donovan, J. A.; Wange, R. L.; Langdon, W. Y. Journal of Biological Chemistry, Vol. 269, Issue 37 https://doi.org/10.1016/S0021-9258(17)31595-8	journal	September 1994
SH3 domains of the adapter molecule Grb2 complex with two proteins in T cells: the guanine nucleotide exchange protein Sos and a 75-kDa protein that is a substrate for T cell antigen receptor-activated tyrosine kinases. Reif, K.; Buday, L.; Downward, J. Journal of Biological Chemistry, Vol. 269, Issue 19 https://doi.org/10.1016/S0021-9258(17)36757-1	journal	May 1994
Sequence-structure Signals of 3D Domain Swapping in Proteins Dehouck, Yves; Biot, Christophe; Gilis, Dimitri Journal of Molecular Biology, Vol. 330, Issue 5 https://doi.org/10.1016/S0022-2836(03)00614-4	journal	July 2003
Structure and specificity of the SH2 domain Waksman, Gabriel; Kuriyan, John Cell, Vol. 116 https://doi.org/10.1016/S0092-8674(04)00043-1	journal	January 2004
Gene dosage-dependent functions for phosphotyrosine-Grb2 signaling during mammalian tissue morphogenesis Saxton, Tracy M.; Cheng, Alec M.; Ong, Siew Hwa Current Biology, Vol. 11, Issue 9 https://doi.org/10.1016/S0960-9822(01)00198-1	journal	May 2001
Structural and energetic aspects of Grb2-SH2 domain-swapping Benfield, Aaron P.; Whiddon, Benjamin B.; Clements, John H. Archives of Biochemistry and Biophysics, Vol. 462, Issue 1 https://doi.org/10.1016/j.abb.2007.03.010	journal	June 2007
Grb2 adaptor undergoes conformational change upon dimerization McDonald, Caleb B.; Seldeen, Kenneth L.; Deegan, Brian J. Archives of Biochemistry and Biophysics, Vol. 475, Issue 1 https://doi.org/10.1016/j.abb.2008.04.008	journal	July 2008
Regions outside of conserved PxxPxR motifs drive the high affinity interaction of GRB2 with SH3 domain ligands Bartelt, Rebekah R.; Light, Jonathan; Vacaflores, Aldo Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1853, Issue 10 https://doi.org/10.1016/j.bbamcr.2015.06.002	journal	October 2015
Myogenic differentiation depends on the interplay of Grb2 and N-WASP Mitra, Payal; Thanabalu, Thirumaran Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1864, Issue 3 https://doi.org/10.1016/j.bbamcr.2016.12.011	journal	March 2017
A Simple Model of Protein Domain Swapping in Crowded Cellular Environments Woodard, Jaie C.; Dunatunga, Sachith; Shakhnovich, Eugene I. Biophysical Journal, Vol. 110, Issue 11 https://doi.org/10.1016/j.bpj.2016.04.033	journal	June 2016
Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation Duda, David M.; Borg, Laura A.; Scott, Daniel C. Cell, Vol. 134, Issue 6 https://doi.org/10.1016/j.cell.2008.07.022	journal	September 2008
Inhibition of Basal FGF Receptor Signaling by Dimeric Grb2 Lin, Chi-Chuan; Melo, Fernando A.; Ghosh, Ragini Cell, Vol. 149, Issue 7 https://doi.org/10.1016/j.cell.2012.04.033	journal	June 2012
Interaction Domains of Sos1/Grb2 Are Finely Tuned for Cooperative Control of Embryonic Stem Cell Fate Findlay, Greg M.; Smith, Matthew J.; Lanner, Fredrik Cell, Vol. 152, Issue 5 https://doi.org/10.1016/j.cell.2013.01.056	journal	February 2013
Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2 SH2 Domain Phan, Jason; Shi, Zhen-Dan; Burke, Terrence R. Journal of Molecular Biology, Vol. 353, Issue 1 https://doi.org/10.1016/j.jmb.2005.08.037	journal	October 2005
The Structure and Conformation of Lys63-Linked Tetraubiquitin Datta, Ajit B.; Hura, Greg L.; Wolberger, Cynthia Journal of Molecular Biology, Vol. 392, Issue 5 https://doi.org/10.1016/j.jmb.2009.07.090	journal	October 2009
Free State Conformational Sampling of the SAM-I Riboswitch Aptamer Domain Stoddard, Colby D.; Montange, Rebecca K.; Hennelly, Scott P. Structure, Vol. 18, Issue 7 https://doi.org/10.1016/j.str.2010.04.006	journal	July 2010
A High-Affinity Arg-X-X-Lys SH3 Binding Motif Confers Specificity for the Interaction between Gads and SLP-76 in T Cell Signaling Berry, Donna M.; Nash, Piers; Liu, Stanley K. -W. Current Biology, Vol. 12, Issue 15 https://doi.org/10.1016/s0960-9822(02)01038-2	journal	August 2002
The hematopoietic-specific adaptor protein Gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors Liu, Stanley K.; Fang, Nan; Koretzky, Gary A. Current Biology, Vol. 9, Issue 2 https://doi.org/10.1016/s0960-9822(99)80017-7	journal	January 1999
The Domain-Swapped Dimer of Cyanovirin-N Is in a Metastable Folded State Barrientos, Laura G.; Louis, John M.; Botos, Istvan Structure, Vol. 10, Issue 5 https://doi.org/10.1016/s0969-2126(02)00758-x	journal	May 2002
The Unfolding Story of Three-Dimensional Domain Swapping Rousseau, Frederic; Schymkowitz, Joost W. H.; Itzhaki, Laura S. Structure, Vol. 11, Issue 3 https://doi.org/10.1016/s0969-2126(03)00029-7	journal	March 2003
Proline-dependent oligomerization with arm exchange Bergdoll, Marc; Remy, Marie-Hélène; Cagnon, Christine Structure, Vol. 5, Issue 3 https://doi.org/10.1016/s0969-2126(97)00196-2	journal	March 1997
Structural Basis for Specific Binding of the Gads SH3 Domain to an RxxK Motif-Containing SLP-76 Peptide Liu, Qin; Berry, Donna; Nash, Piers Molecular Cell, Vol. 11, Issue 2 https://doi.org/10.1016/s1097-2765(03)00046-7	journal	February 2003
X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution Putnam, Christopher D.; Hammel, Michal; Hura, Greg L. Quarterly Reviews of Biophysics, Vol. 40, Issue 3 https://doi.org/10.1017/s0033583507004635	journal	August 2007
Dimer Formation through Domain Swapping in the Crystal Structure of the Grb2-SH2−Ac-pYVNV Complex ^‡ Schiering, Nikolaus; Casale, Elena; Caccia, Paolo Biochemistry, Vol. 39, Issue 44 https://doi.org/10.1021/bi0012336	journal	November 2000
Folding and Association of the Human Cell Cycle Regulatory Proteins ckshs1 and ckshs2 Seeliger, Markus A.; Schymkowitz, Joost W. H.; Rousseau, Frederic Biochemistry, Vol. 41, Issue 4 https://doi.org/10.1021/bi0113465	journal	December 2001
Binding Specificity of Multiprotein Signaling Complexes Is Determined by Both Cooperative Interactions and Affinity Preferences ^† Houtman, Jon C. D.; Higashimoto, Yuichiro; Dimasi, Nazzareno Biochemistry, Vol. 43, Issue 14 https://doi.org/10.1021/bi0357311	journal	April 2004
Human DNA Ligase III Recognizes DNA Ends by Dynamic Switching between Two DNA-Bound States Cotner-Gohara, Elizabeth; Kim, In-Kwon; Hammel, Michal Biochemistry, Vol. 49, Issue 29 https://doi.org/10.1021/bi100503w	journal	July 2010
Nuclear Magnetic Resonance Solution Structure of the Growth Factor Receptor-Bound Protein 2 Src Homology 2 Domain Thornton, Kevin H.; Mueller, W. Tom; McConnell, Patrick Biochemistry, Vol. 35, Issue 36 https://doi.org/10.1021/bi952615s	journal	January 1996
Structural and Conformational Requirements for High-Affinity Binding to the SH2 Domain of Grb2 Ettmayer, Peter; France, Dennis; Gounarides, John Journal of Medicinal Chemistry, Vol. 42, Issue 6 https://doi.org/10.1021/jm9811007	journal	March 1999
Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases Rozakis-Adcock, M.; McGlade, J.; Mbamalu, G. Nature, Vol. 360, Issue 6405 https://doi.org/10.1038/360689a0	journal	December 1992
Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck Eck, Michael J.; Shoelson, Steven E.; Harrison, Stephen C. Nature, Vol. 362, Issue 6415 https://doi.org/10.1038/362087a0	journal	March 1993
Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation Egan, Sean E.; Giddings, Barton W.; Brooks, Mary W. Nature, Vol. 363, Issue 6424 https://doi.org/10.1038/363045a0	journal	May 1993
The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1 Rozakis-Adcock, Maria; Fernley, Ross; Wade, John Nature, Vol. 363, Issue 6424 https://doi.org/10.1038/363083a0	journal	May 1993
Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras Gale, Nicholas W.; Kaplan, Susan; Lowenstein, Eve J. Nature, Vol. 363, Issue 6424 https://doi.org/10.1038/363088a0	journal	May 1993
SH2 domain specificity and activity modified by a single residue Marengere, Luc E. M.; Songyang, Zhou; Gish, Gerald D. Nature, Vol. 369, Issue 6480 https://doi.org/10.1038/369502a0	journal	June 1994
Optimization of methods for the genetic modification of human T cells Bilal, Mahmood Y.; Vacaflores, Aldo; Houtman, Jon CD Immunology & Cell Biology, Vol. 93, Issue 10 https://doi.org/10.1038/icb.2015.59	journal	June 2015
Grb2 monomer–dimer equilibrium determines normal versus oncogenic function Ahmed, Zamal; Timsah, Zahra; Suen, Kin M. Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms8354	journal	June 2015
Ab initio electron density determination directly from solution scattering data Grant, Thomas D. Nature Methods, Vol. 15, Issue 3 https://doi.org/10.1038/nmeth.4581	journal	January 2018
Structural basis for specificity of GRB2-SH2 revealed by a novel ligand binding mode Rahuel, Joseph; Gay, Brigitte; Erdmann, Dirk Nature Structural Biology, Vol. 3, Issue 7 https://doi.org/10.1038/nsb0796-586	journal	July 1996
Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1 Houtman, Jon C. D.; Yamaguchi, Hiroshi; Barda-Saad, Mira Nature Structural & Molecular Biology, Vol. 13, Issue 9 https://doi.org/10.1038/nsmb1133	journal	August 2006
Grb2 binds to PTEN and regulates its nuclear translocation to maintain the genomic stability in DNA damage response Hou, Bolin; Xu, Shanshan; Xu, Yang Cell Death & Disease, Vol. 10, Issue 8 https://doi.org/10.1038/s41419-019-1762-3	journal	July 2019
Efficient T-cell receptor signaling requires a high-affinity interaction between the Gads C-SH3 domain and the SLP-76 RxxK motif Seet, Bruce T.; Berry, Donna M.; Maltzman, Jonathan S. The EMBO Journal, Vol. 26, Issue 3 https://doi.org/10.1038/sj.emboj.7601535	journal	January 2007
Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells Paz, Pedro E.; Wang, Soujuan; Clarke, Holly Biochemical Journal, Vol. 356, Issue 2 https://doi.org/10.1042/0264-6021:3560461	journal	June 2001
Grb2 functions at the top of the T-cell antigen receptor–induced tyrosine kinase cascade to control thymic selection Jang, Ihn Kyung; Zhang, Jinping; Chiang, Yungping J. Proceedings of the National Academy of Sciences, Vol. 107, Issue 23 https://doi.org/10.1073/pnas.0905039107	journal	May 2010
Three-dimensional domain swapping in p13suc1 occurs in the unfolded state and is controlled by conserved proline residues Rousseau, F.; Schymkowitz, J. W. H.; Wilkinson, H. R. Proceedings of the National Academy of Sciences, Vol. 98, Issue 10 https://doi.org/10.1073/pnas.101542098	journal	May 2001
Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries. Matuoka, K.; Shibata, M.; Yamakawa, A. Proceedings of the National Academy of Sciences, Vol. 89, Issue 19 https://doi.org/10.1073/pnas.89.19.9015	journal	October 1992
Interaction of Grb2 via its Src homology 3 domains with synaptic proteins including synapsin I. McPherson, P. S.; Czernik, A. J.; Chilcote, T. J. Proceedings of the National Academy of Sciences, Vol. 91, Issue 14 https://doi.org/10.1073/pnas.91.14.6486	journal	July 1994
Molecular Cloning of SLP-76, a 76-kDa Tyrosine Phosphoprotein Associated with Grb2 in T Cells Jackman, Janet K.; Motto, David G.; Sun, Qiming Journal of Biological Chemistry, Vol. 270, Issue 13 https://doi.org/10.1074/jbc.270.13.7029	journal	March 1995
SH3 Domain-mediated Interaction of Dystroglycan and Grb2 Yang, Bin; Jung, Daniel; Motto, David Journal of Biological Chemistry, Vol. 270, Issue 20 https://doi.org/10.1074/jbc.270.20.11711	journal	May 1995
A Comparison of the Interaction of Shc and the Tyrosine Kinase ZAP-70 with the T Cell Antigen Receptor ζ Chain Tyrosine-based Activation Motif Osman, Narin; Lucas, Susan C.; Turner, Helen Journal of Biological Chemistry, Vol. 270, Issue 23 https://doi.org/10.1074/jbc.270.23.13981	journal	June 1995
Interactions of Cbl with Two Adaptor Proteins, Grb2 and Crk, upon T Cell Activation Buday, László; Khwaja, Asim; Sipeki, Szabolcs Journal of Biological Chemistry, Vol. 271, Issue 11 https://doi.org/10.1074/jbc.271.11.6159	journal	March 1996
Interaction between Sam68 and Src Family Tyrosine Kinases, Fyn and Lck, in T Cell Receptor Signaling Fusaki, Noemi; Iwamatsu, Akihiro; Iwashima, Makio Journal of Biological Chemistry, Vol. 272, Issue 10 https://doi.org/10.1074/jbc.272.10.6214	journal	March 1997
SH3 Domain-dependent Association of Huntingtin with Epidermal Growth Factor Receptor Signaling Complexes Liu, Ya Fang; Deth, Richard C.; Devys, Dider Journal of Biological Chemistry, Vol. 272, Issue 13 https://doi.org/10.1074/jbc.272.13.8121	journal	March 1997
Growth Factor Receptor-bound Protein 2 SH2/SH3 Domain Binding to CD28 and Its Role in Co-signaling Kim, Hong-Hee; Tharayil, Mary; Rudd, Christopher E. Journal of Biological Chemistry, Vol. 273, Issue 1 https://doi.org/10.1074/jbc.273.1.296	journal	January 1998
Grb2 and Its Apoptotic Isoform Grb3-3 Associate with Heterogeneous Nuclear Ribonucleoprotein C, and These Interactions Are Modulated by Poly(U) RNA Romero, Francisco; Ramos-Morales, Francisco; Domı́nguez, Africa Journal of Biological Chemistry, Vol. 273, Issue 13 https://doi.org/10.1074/jbc.273.13.7776	journal	March 1998
Grb2 Forms an Inducible Protein Complex with CD28 through a Src Homology 3 Domain-Proline Interaction Okkenhaug, Klaus; Rottapel, Robert Journal of Biological Chemistry, Vol. 273, Issue 33 https://doi.org/10.1074/jbc.273.33.21194	journal	August 1998
Association of Grb2, Gads, and Phospholipase C-γ1 with Phosphorylated LAT Tyrosine Residues Zhang, Weiguo; Trible, Ronald P.; Zhu, Minghua Journal of Biological Chemistry, Vol. 275, Issue 30 https://doi.org/10.1074/jbc.M000404200	journal	July 2000
Identification of the Minimal Tyrosine Residues Required for Linker for Activation of T Cell Function Lin, Joseph; Weiss, Arthur Journal of Biological Chemistry, Vol. 276, Issue 31 https://doi.org/10.1074/jbc.M102221200	journal	June 2001
The Phosphotyrosine Peptide Binding Specificity of Nck1 and Nck2 Src Homology 2 Domains Frese, Susanne; Schubert, Wolf-Dieter; Findeis, Antje C. Journal of Biological Chemistry, Vol. 281, Issue 26 https://doi.org/10.1074/jbc.M512917200	journal	April 2006
Specific Grb2-mediated Interactions Regulate Clathrin-dependent Endocytosis of the cMet-tyrosine Kinase Li, Ning; Lorinczi, Marta; Ireton, Keith Journal of Biological Chemistry, Vol. 282, Issue 23 https://doi.org/10.1074/jbc.M610835200	journal	June 2007
GrpL, a Grb2-related Adaptor Protein, Interacts with SLP-76 to Regulate Nuclear Factor of Activated T Cell Activation Law, Che-Leung; Ewings, Maria K.; Chaudhary, Preet M. The Journal of Experimental Medicine, Vol. 189, Issue 8 https://doi.org/10.1084/jem.189.8.1243	journal	April 1999
Wiskott-Aldrich syndrome protein is associated with the adapter protein Grb2 and the epidermal growth factor receptor in living cells. She, H. Y.; Rockow, S.; Tang, J. Molecular Biology of the Cell, Vol. 8, Issue 9 https://doi.org/10.1091/mbc.8.9.1709	journal	September 1997
Grb2 Regulates Internalization of EGF Receptors through Clathrin-coated Pits Jiang, Xuejun; Huang, Fangtian; Marusyk, Andriy Molecular Biology of the Cell, Vol. 14, Issue 3 https://doi.org/10.1091/mbc.e02-08-0532	journal	March 2003
Cbl-dependent Ubiquitination Is Required for Progression of EGF Receptors into Clathrin-coated Pits Stang, Espen; Blystad, Frøydis D.; Kazazic, Maja Molecular Biology of the Cell, Vol. 15, Issue 8 https://doi.org/10.1091/mbc.e04-01-0041	journal	August 2004
YASARA View—molecular graphics for all devices—from smartphones to workstations Krieger, Elmar; Vriend, Gert Bioinformatics, Vol. 30, Issue 20 https://doi.org/10.1093/bioinformatics/btu426	journal	July 2014
Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling Li, S. The EMBO Journal, Vol. 20, Issue 23 https://doi.org/10.1093/emboj/20.23.6793	journal	December 2001
Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76 Harkiolaki, M. The EMBO Journal, Vol. 22, Issue 11 https://doi.org/10.1093/emboj/cdg258	journal	June 2003
CD28 stimulation triggers NF- B activation through the CARMA1-PKC -Grb2/Gads axis Takeda, K.; Harada, Y.; Watanabe, R. International Immunology, Vol. 20, Issue 12 https://doi.org/10.1093/intimm/dxn108	journal	October 2008
SASBDB, a repository for biological small-angle scattering data Valentini, Erica; Kikhney, Alexey G.; Previtali, Gianpietro Nucleic Acids Research, Vol. 43, Issue D1 https://doi.org/10.1093/nar/gku1047	journal	October 2014
Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy Dharmawardana, Pathirage G.; Peruzzi, Benedetta; Giubellino, Alessio Anti-Cancer Drugs, Vol. 17, Issue 1 https://doi.org/10.1097/01.cad.0000185180.72604.ac	journal	January 2006
Structure of the interleukin-2 tyrosine kinase Src homology 2 domain; comparison between X-ray and NMR-derived structures Joseph, Raji E.; Ginder, Nathaniel D.; Hoy, Julie A. Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 68, Issue 2 https://doi.org/10.1107/S1744309111049761	journal	January 2012
ATSAS 2.8 : a comprehensive data analysis suite for small-angle scattering from macromolecular solutions Franke, D.; Petoukhov, M. V.; Konarev, P. V. Journal of Applied Crystallography, Vol. 50, Issue 4 https://doi.org/10.1107/s1600576717007786	journal	June 2017
BioXTAS RAW : improvements to a free open-source program for small-angle X-ray scattering data reduction and analysis Hopkins, Jesse Bennett; Gillilan, Richard E.; Skou, Soren Journal of Applied Crystallography, Vol. 50, Issue 5 https://doi.org/10.1107/s1600576717011438	journal	September 2017
ATSAS 3.0 : expanded functionality and new tools for small-angle scattering data analysis Manalastas-Cantos, Karen; Konarev, Petr V.; Hajizadeh, Nelly R. Journal of Applied Crystallography, Vol. 54, Issue 1 https://doi.org/10.1107/s1600576720013412	journal	February 2021
Studying multisite binary and ternary protein interactions by global analysis of isothermal titration calorimetry data in SEDPHAT: Application to adaptor protein complexes in cell signaling Houtman, Jon C. D.; Brown, Patrick H.; Bowden, Brent Protein Science, Vol. 16, Issue 1 https://doi.org/10.1110/ps.062558507	journal	January 2007
MicroRNA‐1258 suppresses tumour progression via GRB2/Ras/Erk pathway in non‐small‐cell lung cancer Jiang, Wei; Wei, Ke; Pan, Chunfeng Cell Proliferation, Vol. 51, Issue 6 https://doi.org/10.1111/cpr.12502	journal	August 2018
The B‐lymphoid Grb2 interaction code Neumann, Konstantin; Oellerich, Thomas; Urlaub, Henning Immunological Reviews, Vol. 232, Issue 1 https://doi.org/10.1111/j.1600-065X.2009.00845.x	journal	October 2009
Structural Mechanism of Abscisic Acid Binding and Signaling by Dimeric PYR1 Nishimura, N.; Hitomi, K.; Arvai, A. S. Science, Vol. 326, Issue 5958 https://doi.org/10.1126/science.1181829	journal	October 2009
Crystal structure of the mammalian Grb2 adaptor Maignan, S.; Guilloteau, J.; Fromage, N. Science, Vol. 268, Issue 5208 https://doi.org/10.1126/science.7716522	journal	April 1995
Dimerization of the adaptor Gads facilitates antigen receptor signaling by promoting the cooperative binding of Gads to the adaptor LAT Sukenik, Sigalit; Frushicheva, Maria P.; Waknin-Lellouche, Cecilia Science Signaling, Vol. 10, Issue 498 https://doi.org/10.1126/scisignal.aal1482	journal	September 2017
Differential Inhibition of Signaling Pathways by Dominant-Negative SH2/SH3 Adapter Proteins Tanaka, Masamitsu; Gupta, Ruchika; Mayer, Bruce J. Molecular and Cellular Biology, Vol. 15, Issue 12 https://doi.org/10.1128/mcb.15.12.6829	journal	December 1995
Activation of the Epidermal Growth Factor (EGF) Receptor Induces Formation of EGF Receptor- and Grb2-Containing Clathrin-Coated Pits Johannessen, Lene E.; Pedersen, Nina Marie; Pedersen, Ketil Winther Molecular and Cellular Biology, Vol. 26, Issue 2 https://doi.org/10.1128/mcb.26.2.389-401.2006	journal	January 2006
MiR-433-3p Inhibits Proliferation and Invasion of Esophageal Squamous Cell Carcinoma by Targeting GRB2 Shi, Qizhong; Wang, Yongling; Mu, Yonghui Cellular Physiology and Biochemistry, Vol. 46, Issue 5 https://doi.org/10.1159/000489548	journal	January 2018
AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling Towler, Mhairi C.; Hardie, D. Grahame Circulation Research, Vol. 100, Issue 3 https://doi.org/10.1161/01.Res.0000256090.42690.05	journal	February 2007
Mitogen requirements for the in vitro propagation of cutaneous T-cell lymphomas Gazdar, Af; Carney, Dn; Bunn, Pa Blood, Vol. 55, Issue 3 https://doi.org/10.1182/blood.V55.3.409.409	journal	March 1980
Grb2 signaling in cell motility and cancer Giubellino, Alessio; Burke, Terrence R.; Bottaro, Donald P. Expert Opinion on Therapeutic Targets, Vol. 12, Issue 8 https://doi.org/10.1517/14728222.12.8.1021	journal	July 2008
The epidermal growth factor receptor family Bazley, L. A.; Gullick, W. J. Endocrine-Related Cancer, Vol. 12, Issue Supplement_1 https://doi.org/10.1677/erc.1.01032	journal	July 2005
Long noncoding RNA AC092171.4 promotes hepatocellular carcinoma progression by sponging microRNA-1271 and upregulating GRB2 Sun, Chengjun; Huang, Shanzhou; Hou, Yuchen Aging, Vol. 12, Issue 14 https://doi.org/10.18632/aging.103419	journal	July 2020
mir-329 restricts tumor growth by targeting grb2 in pancreatic cancer Wang, Xinjing; Lu, Xiongxiong; Zhang, Tian Oncotarget, Vol. 7, Issue 16 https://doi.org/10.18632/oncotarget.7375	journal	February 2016
Structural and functional properties of Grb2 SH2 dimer in CD28 binding Hosoe, Yuhi; Numoto, Nobutaka; Inaba, Satomi Biophysics and Physicobiology, Vol. 16, Issue 0 https://doi.org/10.2142/biophysico.16.0_80	journal	January 2019
Quantitative analysis by surface plasmon resonance of CD28 interaction with cytoplasmic adaptor molecules Grb2, Gads and p85 PI3K Higo, Kunitake; Oda, Masayuki; Morii, Hisayuki Immunological Investigations, Vol. 43, Issue 3 https://doi.org/10.3109/08820139.2013.875039	journal	January 2014
The N-Terminal SH3 Domain of Grb2 is Required for Endosomal Localization of AβPP Raychaudhuri, Mithu; Roy, Kasturi; Das, Samir Journal of Alzheimer's Disease, Vol. 32, Issue 2 https://doi.org/10.3233/JAD-2012-120388	journal	October 2012
GRB2 Nucleates T Cell Receptor-Mediated LAT Clusters That Control PLC-γ1 Activation and Cytokine Production Bilal, Mahmood Yousif; Houtman, Jon C. D. Frontiers in Immunology, Vol. 6 https://doi.org/10.3389/fimmu.2015.00141	journal	March 2015
Influence of point mutations on the stability, dimerization, and oligomerization of human cystatin C and its L68Q variant Szymańska, Aneta; Jankowska, Elżbieta; Orlikowska, Marta Frontiers in Molecular Neuroscience, Vol. 5 https://doi.org/10.3389/fnmol.2012.00082	journal	January 2012
Overexpression of GRB2 Enhances Epithelial to Mesenchymal Transition of A549 Cells by Upregulating SNAIL Expression Mitra, Payal; Kalailingam, Pazhanichamy; Tan, Hui Bing Cells, Vol. 7, Issue 8 https://doi.org/10.3390/cells7080097	journal	August 2018
Minimal Requirement of Tyrosine Residues of Linker for Activation of T Cells in TCR Signaling and Thymocyte Development Zhu, Minghua; Janssen, Erin; Zhang, Weiguo The Journal of Immunology, Vol. 170, Issue 1 https://doi.org/10.4049/jimmunol.170.1.325	journal	January 2003

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