The metastasis gene NEDD9 product acts through integrin beta 3 and Src to promote mesenchymal motility and inhibit amoeboid motility

Jessica Ahn, Victoria Sanz Moreno, Christopher J. Marshall

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

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 beta 3 signalling, which leads to elevated phosphorylation of integrin beta 3. 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.

Original languageEnglish
Pages (from-to)1814-1826
Number of pages13
JournalJournal of Cell Science
Volume125
Issue number7
Early online date10 Feb 2012
DOIs
Publication statusPublished - 1 Apr 2012

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