Growth factor receptor-bound protein 2 SH2/SH3 domain binding to CD28 and its role in co-signaling

被引:101
作者
Kim, HH
Tharayil, M
Rudd, CE
机构
[1] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.273.1.296
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The co-stimulatory antigen CD28 has been shown to bind to several intracellular proteins including phosphatidylinositol S-kinase, growth factor receptor-bound protein 2 (Grb2), and ITK, Paradoxically, Grb2 and phosphatidylinositol 3-kinase binding has been mapped to a similar pYMNM motif within the CD28 cytoplasmic tail, Given the importance of CD28 co-signaling to T cell function, questions exist regarding the mechanism by which Grb2 binds to CD28, and whether the interaction plays a role in co-stimulation. To biochemically characterize Grb2/CD28 binding, we initially utilized glutathione S-transferase-Grb2 fusion proteins carrying inactivating mutations within the SH2 and SH3 domains of Grb2, and assessed their ability to bind to CD28, In vitro binding experiments indicated that the Grb2 SH2 domain is critical for the association, while the SH3 domain plays an additional role in facilitating optimal binding, Enhanced binding via the SH3 domains was not observed when the C-terminal PXXP motif within CD28 was disrupted, thereby indicating that both SH2 and SH3 domains contribute to CD28 binding. Mutations that alter Grb2 binding were found to block the CD28-dependent interleukin-a production. Further, tyrosine phosphorylation of Vav and the costimulation-dependent activation of Jun N-terminal kinase was blocked in cells defective in CD28/Grb2 binding. These results provide evidence for an alternate CD28-mediated signaling process involving Grb2 binding to the co-receptor.
引用
收藏
页码:296 / 301
页数:6
相关论文
共 42 条
  • [31] P56(LCK) AND P59(FYN) REGULATE CD28 BINDING TO PHOSPHATIDYLINOSITOL 3-KINASE, GROWTH-FACTOR RECEPTOR-BOUND PROTEIN GRB-2, AND T-CELL-SPECIFIC PROTEIN-TYROSINE KINASE-ITK - IMPLICATIONS FOR T-CELL COSTIMULATION
    RAAB, M
    CAI, YC
    BUNNELL, SC
    HEYECK, SD
    BERG, LJ
    RUDD, CE
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (19) : 8891 - 8895
  • [32] RAMOSMORALES F, 1995, ONCOGENE, V11, P1665
  • [33] THE SH2 AND SH3 DOMAINS OF MAMMALIAN GRB2 COUPLE THE EGF RECEPTOR TO THE RAS ACTIVATOR MSOS1
    ROZAKISADCOCK, M
    FERNLEY, R
    WADE, J
    PAWSON, T
    BOWTELL, D
    [J]. NATURE, 1993, 363 (6424) : 83 - 85
  • [34] ASSOCIATION OF THE SHC AND GRB2/SEM5 SH2-CONTAINING PROTEINS IS IMPLICATED IN ACTIVATION OF THE RAS PATHWAY BY TYROSINE KINASES
    ROZAKISADCOCK, M
    MCGLADE, J
    MBAMALU, G
    PELICCI, G
    DALY, R
    LI, W
    BATZER, A
    THOMAS, S
    BRUGGE, J
    PELICCI, PG
    SCHLESSINGER, J
    PAWSON, T
    [J]. NATURE, 1992, 360 (6405) : 689 - 692
  • [35] Upstream-downstream: CD28 cosignaling pathways and T cell function
    Rudd, CE
    [J]. IMMUNITY, 1996, 4 (06) : 527 - 534
  • [36] T-CELL ANTIGEN CD28 BINDS TO THE GRB-2/SOS COMPLEX, REGULATORS OF P21(RAS)
    SCHNEIDER, H
    CAI, YC
    PRASAD, KVS
    SHOELSON, SE
    RUDD, CE
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1995, 25 (04) : 1044 - 1050
  • [37] JNK IS INVOLVED IN SIGNAL INTEGRATION DURING COSTIMULATION OF T-LYMPHOCYTES
    SU, B
    JACINTO, E
    HIBI, M
    KALLUNKI, T
    KARIN, M
    BEN-NERIAH, Y
    [J]. CELL, 1994, 77 (05) : 727 - 736
  • [38] Involvement of Src-homology-2-domain-containing protein-tyrosine phosphatase 2 in T cell activation
    Tailor, P
    Jascur, T
    Williams, S
    vonWillebrand, M
    Couture, C
    Mustelin, T
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1996, 237 (03): : 736 - 742
  • [39] CD28 ACTIVATION PATHWAY REGULATES THE PRODUCTION OF MULTIPLE T-CELL-DERIVED LYMPHOKINES CYTOKINES
    THOMPSON, CB
    LINDSTEN, T
    LEDBETTER, JA
    KUNKEL, SL
    YOUNG, HA
    EMERSON, SG
    LEIDEN, JM
    JUNE, CH
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (04) : 1333 - 1337
  • [40] STIMULATION OF CD28 TRIGGERS AN ASSOCIATION BETWEEN CD28 AND PHOSPHATIDYLINOSITOL 3-KINASE IN JURKAT T-CELLS
    TRUITT, KE
    HICKS, CM
    IMBODEN, JB
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1994, 179 (03) : 1071 - 1076