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Molecular and Cellular Biology, April 2006, p. 2479-2489, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2479-2489.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Dok-1 Independently Attenuates Ras/Mitogen-Activated Protein Kinase and Src/c-Myc Pathways To Inhibit Platelet-Derived Growth Factor-Induced Mitogenesis

Mingming Zhao ,^1,, Justyna A. Janas,^1, Masaru Niki,² Pier Paolo Pandolfi,² and Linda Van Aelst^1*

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724,¹ Department of Human Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10021²

Received 8 November 2005/ Returned for modification 23 December 2005/ Accepted 16 January 2006

The Dok adaptor proteins play key regulatory roles in receptor and non-receptor kinase-initiated signaling pathways. Dok-1, the prototype member of this family, negatively regulates cell proliferation elicited by numerous growth factors, including platelet-derived growth factor (PDGF). However, how Dok-1 exerts its negative effect on mitogenesis has remained elusive. Using Dok-1 knockout cells and Dok-1 mutants deficient in binding to specific Dok-1-interacting proteins, we show that Dok-1 interferes with PDGF-stimulated c-myc induction and Ras/mitogen-activated protein kinase (MAPK) activation by tethering different signaling components to the cell membrane. Specifically, Dok-1 attenuates PDGF-elicited c-myc induction by recruiting Csk to active Src kinases, whereupon their activities and consequent c-myc induction are diminished. On the other hand, Dok-1 negatively regulates PDGF-induced MAPK activation by acting on Ras-GAP and at least one other Dok-1-interacting protein. Importantly, we demonstrate that Dok-1's actions on both of these signaling pathways contribute to its inhibitory effect on mitogenesis. Our data suggest a mechanistic basis for the inhibitory effect of Dok-1 on growth factor-induced mitogenesis and its role as a tumor suppressor.

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* Corresponding author. Mailing address: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724. Phone: (516) 367-6829. Fax: (516) 367-8815. E-mail: vanaelst{at}cshl.edu.

M.Z. and J.A.J. contributed equally to this work.

Present address: Developmental Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10021.

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Molecular and Cellular Biology, April 2006, p. 2479-2489, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2479-2489.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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