title: Promotion of invasion by mutant RAS is dependent on activation of the WASF3 metastasis promoter gene.
abstract: Metastasis represents an end stage in the evolution of cancer progression and has been related to specific genetic pathways. Overexpression of mutant RAS in particular appears to promote invasion and metastasis, although exactly how this occurs has not been well characterized. It was previously showed that activation of the WASF3 protein regulates actin cytoskeleton dynamics that promote invasion. In this report, how WASF3 overexpression interacts with mutant RAS to increase invasion and metastasis was investigated. The ability of RAS to promote invasion and metastasis was shown to be dependent on WASF3 activation in a PI3K and AKT dependent manner. Proteomics analysis demonstrates the presence of AKT in the WASF3 immunocomplex which is enhanced by overexpression of mutant RAS. During these processes activation of ERK1/2 is not affected by loss of WASF3 expression. Analysis of the relative involvement of p85 and p110 in the WASF3 complex demonstrates that mutant RAS promotes dissociation of p85 promoting activation of p110. These studies provide a deeper understanding of the critical role for WASF3 in facilitating increased invasion potential in cancer cells expressing mutant RAS and supports the idea that targeting WASF3 in metastatic cells overexpressing RAS may be used to suppress invasion and metastasis.
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, Georgia, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, Georgia, USA.
authors.forename: Lambert
authors.initials: L
authors.lastname: Ngoka
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, Georgia, USA.
authors.forename: John K
authors.identifier: 0000-0002-2079-5950
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics*
chemical_list: C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt