This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Slyke, P. Articles by Dumont, D. J. Search for Related Content PubMed PubMed Citation Articles by Van Slyke, P. Articles by Dumont, D. J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 2005, p. 3831-3841, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3831-3841.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Dok-R Mediates Attenuation of Epidermal Growth Factor-Dependent Mitogen-Activated Protein Kinase and Akt Activation through Processive Recruitment of c-Src and Csk

Division of Molecular and Cellular Biology Research, Sunnybrook and Women's Research Institute, Toronto, Ontario, Canada M4N 3M5,¹ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada,² Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada,³ Heart & Stroke/Richard Lewar Centre of Excellence, Faculty of Medicine, University of Toronto, Ontario, Canada⁴

Received 24 June 2004/ Returned for modification 19 August 2004/ Accepted 23 December 2004

Dok-R has previously been shown to associate with the epidermal growth factor receptor (EGFR) and become tyrosine phosphorylated in response to EGF stimulation. The recruitment of Dok-R to the EGFR, which is mediated through its phosphotyrosine binding (PTB) domain, results in attenuation of mitogen-activated protein kinase (MAPK) activation. Dok-R's ability to attenuate EGF-driven MAPK activation is independent of its ability to recruit rasGAP, a known attenuator of MAPK activity, suggesting an alternate Dok-R-mediated pathway. Herein, we have determined the structural determinants within Dok-R that are required for its ability to attenuate EGF signaling and to associate with c-Src and with the Src family kinase (SFK)-inhibitory kinase, Csk. We demonstrate that Dok-R associates constitutively with c-Src through an SH3-dependent interaction and that this association is essential to Dok-R's ability to attenuate c-Src activity and diminish MAPK and Akt/PKB activity. We further illustrate that EGF-dependent phosphorylation of Dok-R requires SFK activity and, more specifically, that SFK-dependent phosphorylation of tyrosine 402 on Dok-R facilitates the inducible recruitment of Csk. We propose that recruitment of Csk to Dok-R serves to bring Csk to c-Src and down-regulate its activity, resulting in a concomitant attenuation of MAPK and Akt/PKB activity. Furthermore, we demonstrate that Dok-R can abrogate c-Src's ability to protect the breast cancer cell line SKBR3 from anoikis and that an association with c-Src and Csk is required for this activity. Collectively these results demonstrate that Dok-R acts as an EGFR-recruited scaffolding molecule that processively assembles c-Src and Csk to attenuate signaling from the EGFR.

This article has been cited by other articles:

• Yang, K.-J., Shin, S., Piao, L., Shin, E., Li, Y., Park, K. A., Byun, H. S., Won, M., Hong, J., Kweon, G. R., Hur, G. M., Seok, J. H., Chun, T., Brazil, D. P., Hemmings, B. A., Park, J. (2008). Regulation of 3-Phosphoinositide-dependent Protein Kinase-1 (PDK1) by Src Involves Tyrosine Phosphorylation of PDK1 and Src Homology 2 Domain Binding. J. Biol. Chem. 283: 1480-1491 [Abstract] [Full Text]  
• Matteucci, E., Ridolfi, E., Maroni, P., Bendinelli, P., Desiderio, M. A. (2007). c-Src/Histone Deacetylase 3 Interaction Is Crucial for Hepatocyte Growth Factor Dependent Decrease of CXCR4 Expression in Highly Invasive Breast Tumor Cells. Mol Cancer Res 5: 833-845 [Abstract] [Full Text]  
• Dong, S., Corre, B., Foulon, E., Dufour, E., Veillette, A., Acuto, O., Michel, F. (2006). T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J. Exp. Med. 203: 2509-2518 [Abstract] [Full Text]  
• Zhao, M., Janas, J. A., Niki, M., Pandolfi, P. P., Van Aelst, L. (2006). Dok-1 Independently Attenuates Ras/Mitogen-Activated Protein Kinase and Src/c-Myc Pathways To Inhibit Platelet-Derived Growth Factor-Induced Mitogenesis.. Mol. Cell. Biol. 26: 2479-2489 [Abstract] [Full Text]  
• Honma, M., Higuchi, O., Shirakata, M., Yasuda, T., Shibuya, H., Iemura, S.-i., Natsume, T., Yamanashi, Y. (2006). Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein-tyrosine kinases. GENES CELLS 11: 143-151 [Abstract] [Full Text]  
• Kasai, A., Shima, T., Okada, M. (2005). Role of Src family tyrosine kinases in the down-regulation of epidermal growth factor signaling in PC12 cells. GENES CELLS 10: 1175-1187 [Abstract] [Full Text]