Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation

被引:81
作者
Jones, N
Dumont, DJ [1 ]
机构
[1] Sunnybrook & Womens Coll, Hlth Sci Ctr, Div Canc Biol Res, Toronto, ON, Canada
[2] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
基金
英国医学研究理事会;
关键词
D O I
10.1016/S0960-9822(99)80458-8
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
Dok (for downstream of tyrosine kinases) proteins are a newly identified family of docking molecules that are characterized by the presence of an amino-terminal pleckstrin homology (PH) domain, a central putative phosphotyrosine binding (PTB) domain and numerous potential sites of tyrosine phosphorylation [1-6]. Here, we explore the potential role of the Dok family member Dok-R (also known as p56(Dok2) or FRIP) in signaling pathways mediated by the epidermal growth factor (EGF) receptor. An intact PTB domain in Dok-R was critical for its association with two PTB-binding consensus sites on the EGF receptor and the PH domain further contributed to stable in vivo binding and tyrosine phosphorylation of Dok-R, Multiple sites on Dok-R were tyrosine-phosphorylated following EGF stimulation; phosphorylated Tyr276 and Tyr304 are proposed to dock the tandem Src homology 2 (SH2) domains of the p21(Ras) GTPase-activating protein rasGAP and Tyr351 mediates an association with the SH2 domain of the adapter protein Nck. lnterestingly, we have found that Dok-R could attenuate EGF-stimulated mitogen-activated protein (MAP) kinase activation independently of its association with rasGAP. Together, these results suggest that Dok-R has an important role downstream of growth factor receptors as a potential negative regulator of signal transduction.
引用
收藏
页码:1057 / 1060
页数:4
相关论文
共 16 条
  • [1] p62(dok): A constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells
    Carpino, N
    Wisniewski, D
    Strife, A
    Marshak, D
    Kobayashi, R
    Stillman, B
    Clarkson, B
    [J]. CELL, 1997, 88 (02) : 197 - 204
  • [2] Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins
    Di Cristofano, A
    Carpino, N
    Dunant, N
    Friedland, G
    Kobayashi, R
    Strife, A
    Wisniewski, D
    Clarkson, B
    Pandolfi, PP
    Resh, MD
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (09) : 4827 - 4830
  • [3] AUTOPHOSPHORYLATION SITES ON THE EPIDERMAL GROWTH-FACTOR RECEPTOR
    DOWNWARD, J
    PARKER, P
    WATERFIELD, MD
    [J]. NATURE, 1984, 311 (5985) : 483 - 485
  • [4] Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor
    Eck, MJ
    DhePaganon, S
    Trub, T
    Nolte, RT
    Shoelson, SE
    [J]. CELL, 1996, 85 (05) : 695 - 705
  • [5] PHOSPHORYLATION OF GAP AND GAP-ASSOCIATED PROTEINS BY TRANSFORMING AND MITOGENIC TYROSINE KINASES
    ELLIS, C
    MORAN, M
    MCCORMICK, F
    PAWSON, T
    [J]. NATURE, 1990, 343 (6256) : 377 - 381
  • [6] SV40-TRANSFORMED SIMIAN CELLS SUPPORT THE REPLICATION OF EARLY SV40 MUTANTS
    GLUZMAN, Y
    [J]. CELL, 1981, 23 (01) : 175 - 182
  • [7] The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R
    Jones, N
    Dumont, DJ
    [J]. ONCOGENE, 1998, 17 (09) : 1097 - 1108
  • [8] JONES N, 1999, IN PRESS J BIOL CHEM
  • [9] MEASUREMENT OF THE BINDING OF TYROSYL PHOSPHOPEPTIDES TO SH2 DOMAINS - A REAPPRAISAL
    LADBURY, JE
    LEMMON, MA
    ZHOU, M
    GREEN, J
    BOTFIELD, MC
    SCHLESSINGER, J
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (08) : 3199 - 3203
  • [10] Independent SH2-binding sites mediate interaction of Dok-related protein with RasGTPase-activating protein and Nck
    Lock, P
    Casagranda, F
    Dunn, AR
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (32) : 22775 - 22784