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Domain-dependent Function of the rasGAP-binding Protein p62Dok in Cell Signaling

Songyang, Zhou and Yamanashi, Yuji and Liu, Dan and Baltimore, David (2001) Domain-dependent Function of the rasGAP-binding Protein p62Dok in Cell Signaling. Journal of Biological Chemistry, 276 (4). pp. 2459-2465. ISSN 0021-9258. https://resolver.caltech.edu/CaltechAUTHORS:SONjbc01

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Abstract

p62Dok, the rasGAP-binding protein, is a common target of protein-tyrosine kinases. It is one of the major tyrosine-phosphorylated molecules in v-Src-transformed cells. Dok consists of an amino-terminal Pleckstrin homology domain, a putative phosphotyrosine binding domain, and a carboxyl-terminal tail containing multiple tyrosine phosphorylation sites. The importance and function of these sequences in Dok signaling remain largely unknown. We have demonstrated here that the expression of Dok can inhibit cellular transformation by the Src tyrosine kinase. Both the phosphotyrosine binding domain and the carboxyl-terminal tail of Dok (in particular residues 336-363) are necessary for such activity. Using a combinatorial peptide library approach, we have shown that the Dok phosphotyrosine binding domain binds phosphopeptides with the consensus motif of Y/MXXNXL-phosphotyrosine. Furthermore, Dok can homodimerize through its phosphotyrosine binding domain and Tyr146 at the amino-terminal region. Mutations of this domain or Tyr146 that block homodimerization significantly reduce the ability of Dok to inhibit Src transformation. Our results suggest that Dok oligomerization through its multiple domains plays a critical role in Dok signaling in response to tyrosine kinase activation.


Item Type:Article
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, June 22, 2000, and in revised form, October 3, 2000. Originally published In Press as doi:10.1074/jbc.M005504200 on October 19, 2000. We thank Drs. Xiaohong Yang and Zongkai Li for technical assistance. We also thank the Department of Biology, Massachusetts Institute of Technology, for support. This work was supported by the Welch Foundation. Z. S. and Y. Y. contributed equally to this work.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Issue or Number:4
Record Number:CaltechAUTHORS:SONjbc01
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:SONjbc01
Alternative URL:http://dx.doi.org/10.1074/jbc.M005504200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9776
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:14 Mar 2008
Last Modified:03 Oct 2019 00:03

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