Dok-1 independently attenuates Ras/mitogen-activated protein kinase and Src/c-myc pathways to inhibit platelet-derived growth factor-induced mitogenesis

Zhao, M., Janas, J. A. , Niki, M., Pandolfi, P. P., Van Aelst, L. (April 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 (7). pp. 2479-89. ISSN 0270-7306 (Print)

URL: http://www.ncbi.nlm.nih.gov/pubmed/16537894
DOI: 10.1128/mcb.26.7.2479-2489.2006

Abstract

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.

Item Type: Paper
Uncontrolled Keywords: Animals DNA Binding Proteins deficiency metabolism Fibroblasts cytology Gene Expression Regulation genetics Mice Mitogen-Activated Protein Kinases metabolism Mitosis drug effects Mutation genetics NIH 3T3 Cells Phosphoproteins deficiency metabolism Platelet-Derived Growth Factor pharmacology Protein Binding Protein Tyrosine Kinases metabolism Proto-Oncogene Proteins c-myc antagonists & inhibitors/genetics/ metabolism Proto-Oncogene Proteins pp60(c-src metabolism RNA, Messenger genetics metabolism RNA-Binding Proteins metabolism Receptors Platelet Derived Growth Factor metabolism ras Proteins/ metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Dok
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > mitogenesis
CSHL Authors:
Communities: CSHL labs > Van Aelst lab
CSHL Post Doctoral Fellows
Depositing User: CSHL Librarian
Date: April 2006
Date Deposited: 06 Dec 2011 18:25
Last Modified: 02 May 2013 18:37
PMCID: PMC1430334
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22951

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