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The metastasis gene NEDD9 product acts through integrin β3 and Src to promote mesenchymal motility and inhibit amoeboid motility.

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Publication Date
2012-04
ICR Author
Marshall, Christopher
Ahn, Jessica Jung Min
Author
Ahn, J
Sanz-Moreno, V
Marshall, CJ
Type
Journal Article
Metadata
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Abstract
Neural precursor expressed, developmentally down-regulated 9 (NEDD9), a member of the Cas family of signal transduction molecules, is amplified at the genetic level in melanoma, and elevated expression levels have been shown to correlate with melanoma progression and metastasis. NEDD9 interacts with the guanine nucleotide exchange factor DOCK3 to promote Rac activation and the elongated, mesenchymal-type of tumour cell invasion, but the molecular mechanisms through which NEDD9 promotes melanoma metastasis are not fully understood. We show that signalling through increased NEDD9 levels requires integrin β3 signalling, which leads to elevated phosphorylation of integrin β3. This results in increased Src and FAK but decreased ROCK signalling to drive elongated, mesenchymal-type invasion in environments that contain vitronectin. NEDD9 overexpression does not affect ROCK signalling through activation of RhoA but decreases ROCKII signalling through Src-dependent phosphorylation of a negative regulatory site Tyr722. In NEDD9-overexpressing melanoma cells, inhibition of Src with dasatinib results in a switch from Rac-driven elongated, mesenchymal-type invasion to ROCK-dependent rounded, amoeboid invasion. These findings brings into question whether dasatinib would work as a therapeutic agent to block melanoma invasion and metastasis. On the basis of the in vitro data presented here, a combination treatment of dasatinib and a ROCK inhibitor might be a better alternative in order to inhibit both elongated, mesenchymal-type and rounded, amoeboid motility.
URL
https://repository.icr.ac.uk/handle/internal/1733
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  • Closed Research Teams
Version of record
10.1242/jcs.101444
Subject
Tumor Cells, Cultured
Mesoderm
Humans
Melanoma
Neoplasm Metastasis
src-Family Kinases
Adaptor Proteins, Signal Transducing
Integrin beta3
Phosphoproteins
Signal Transduction
Cell Movement
Phosphorylation
Research team
Oncogene
Language
eng
License start date
2012-04
Citation
Journal of cell science, 2012, 125 (Pt 7), pp. 1814 - 1826

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