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The Roles of Akt Isoforms in the Regulation of Podosome Formation in Fibroblasts and Extracellular Matrix Invasion

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L-3N6, Canada
Author to whom correspondence should be addressed.
Present address: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada.
Academic Editor: Scott A. Weed
Cancers 2015, 7(1), 96-111;
Received: 11 October 2014 / Accepted: 22 December 2014 / Published: 7 January 2015
(This article belongs to the Special Issue Cancer Cell Invasion)
Mesenchymal cells employ actin-based membrane protrusions called podosomes and invadopodia for cross-tissue migration during normal human development such as embryogenesis and angiogenesis, and in diseases such as atherosclerosis plaque formation and cancer cell metastasis. The Akt isoforms, downstream effectors of phosphatidylinositol 3 kinase (PI3K), play crucial roles in cell migration and invasion, but their involvement in podosome formation and cell invasion is not known. In this study, we have used Akt1 and/or Akt2 knockout mouse embryonic fibroblasts and Akt3-targeted shRNA to determine the roles of the three Akt isoforms in Src and phorbol ester-induced podosome formation, and extracellular matrix (ECM) digestion. We found that deletion or knockdown of Akt1 significantly reduces Src-induced formation of podosomes and rosettes, and ECM digestion, while suppression of Akt2 has little effect. In contrast, Akt3 knockdown by shRNA increases Src-induced podosome/rosette formation and ECM invasion. These data suggest that Akt1 promotes, while Akt3 suppresses, podosome formation induced by Src, and Akt2 appears to play an insignificant role. Interestingly, both Akt1 and Akt3 suppress, while Akt2 enhances, phorbol ester-induced podosome formation. These data show that Akt1, Akt2 and Akt3 play different roles in podosome formation and ECM invasion induced by Src or phorbol ester, thus underscoring the importance of cell context in the roles of Akt isoforms in cell invasion. View Full-Text
Keywords: Akt; podosome; Src; cell invasion; PDBu Akt; podosome; Src; cell invasion; PDBu
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MDPI and ACS Style

Eves, R.; Oldham, R.; Jia, L.; Mak, A.S. The Roles of Akt Isoforms in the Regulation of Podosome Formation in Fibroblasts and Extracellular Matrix Invasion. Cancers 2015, 7, 96-111.

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