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

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] [2] [3] [4] [5] [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. Interestingly, 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.

Pubmed ID: 10508618

Authors

  • Jones N
  • Dumont DJ

Journal

Current biology : CB

Publication Data

September 23, 1999

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Carrier Proteins
  • Cercopithecus aethiops
  • Enzyme Activation
  • GRB2 Adaptor Protein
  • MAP Kinase Signaling System
  • Molecular Sequence Data
  • Oncogene Proteins
  • Phosphoproteins
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Proteins
  • Receptor, Epidermal Growth Factor
  • Recombinant Fusion Proteins
  • Shc Signaling Adaptor Proteins
  • Transfection
  • src Homology Domains