Portal de Periódicos da CAPES

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

1999; Elsevier BV; Volume: 9; Issue: 18 Linguagem: Inglês

10.1016/s0960-9822(99)80458-8

1879-0445

Nina Jones, Daniel Dumont,

Protein Kinase Regulation and GTPase Signaling

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 [1Carpino N Wisniewski D Strife A Marshak D Kobayashi R Stillman B et al.p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells.Cell. 1997; 88: 197-204Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 2Yamanashi Y Baltimore D Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok.Cell. 1997; 88: 205-211Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 3Jones N Dumont DJ The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R.Oncogene. 1998; 17: 1097-1108Crossref PubMed Scopus (131) Google Scholar, 4Nelms K Snow AL Hu-Li J Paul WE FRIP, a hematopoietic cell-specific rasGAP-interacting protein phosphorylated in response to cytokine stimulation.Immunity. 1998; 9: 13-24Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 5Di Cristofano A Carpino N Dunant N Friedland G Kobayashi R Strife A et al.Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins.J Biol Chem. 1998; 273: 4827-4830Crossref PubMed Scopus (116) Google Scholar, 6Lock P Casagranda F Dunn AR Independent SH2-binding sites mediate interaction of dok-related protein with RasGTPase-activating protein and Nck.J Biol Chem. 1999; 274: 22775-22784Crossref PubMed Scopus (52) Google Scholar]. Here, we explore the potential role of the Dok family member Dok-R (also known as p56Dok2 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 p21Ras 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.