Dok-1 independently attenuates Ras/mitogen-activated protein kinase and Src/c-Myc pathways to inhibit platelet-derived growth factor-induced mitogenesis Journal Article
| Authors: | Zhao, M.; Janas, J. A.; Niki, M.; Pandolfi, P. P.; Van Aelst, L. |
| Article Title: | Dok-1 independently attenuates Ras/mitogen-activated protein kinase and Src/c-Myc pathways to inhibit platelet-derived growth factor-induced mitogenesis |
| 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. Copyright © 2006, American Society for Microbiology. All Rights Reserved. |
| Keywords: | signal transduction; mitogen activated protein kinase; platelet derived growth factor; controlled study; unclassified drug; mutation; dna-binding proteins; nonhuman; protein function; cell proliferation; mitosis; animal cell; mouse; animals; mice; embryo; protein protein interaction; mitogenesis; protein binding; enzyme activation; enzyme activity; protein tyrosine kinase; animalia; gene expression regulation; rna-binding proteins; cancer inhibition; rna, messenger; myc protein; cell membrane; platelet-derived growth factor; fibroblasts; phosphoproteins; ras protein; protein-tyrosine kinases; ras proteins; protein family; mitogen-activated protein kinases; proto-oncogene proteins c-myc; nih 3t3 cells; receptors, platelet-derived growth factor; proto-oncogene proteins pp60(c-src); protein dok 1; adaptor protein |
| Journal Title: | Molecular and Cellular Biology |
| Volume: | 26 |
| Issue: | 7 |
| ISSN: | 0270-7306 |
| Publisher: | American Society for Microbiology |
| Date Published: | 2006-04-01 |
| Start Page: | 2479 |
| End Page: | 2489 |
| Language: | English |
| DOI: | 10.1128/mcb.26.7.2479-2489.2006 |
| PUBMED: | 16537894 |
| PROVIDER: | scopus |
| PMCID: | PMC1430334 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 18" - "Export Date: 4 June 2012" - "CODEN: MCEBD" - "Source: Scopus" |
