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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.

Current biology : CB | Sep 23, 1999

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 RIS Download

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