eEF1A2 activates Akt and stimulates Akt-dependent actin remodeling, invasion and migration

Abstract

eEF1A2 (eukaryotic protein elongation factor 1 alpha 2) is a protein translation factor that is likely a human oncogene by virtue of its capacity to transform mammalian cells and its high expression in tumors of the ovary, breast and lung. Here, we show that expression of eEF1A2 is sufficient to stimulate the formation of filopodia in BT549 human breast cancer cells and non-transformed Rat2 cells. Filopodia formation in eEF1A2-expressing cells is dependent on the activity of phosphatidylinositol-3 kinase (PI3K), and the ROCK and Akt kinases. Furthermore, eEF1A2 expression is sufficient to activate Akt in a PI3K-dependent fashion and inactivation of eEF1A2 by short interfering RNA reduces Akt activity. Using breast cancer cell line BT 549, we show that eEF1A2 expression stimulates cell migration and invasion in a largely PI3K-and Akt-dependent manner. These results suggest that eEF1A2 regulates oncogenesis through Akt and PI3K-dependent cytoskeletal remodeling.

Raf kinases in signal transduction and interaction with translation machinery

“…This effect was also associated with an inhibition of apoptosis of approximately 70% as evaluated by cytofluorimetric analysis (Becton Dickinson; Palo Alto, CA, USA) with propidium iodide (Sigma, St. Louis, MO, USA), thus confirming the oncogenic properties of eEF1A2. Similar behavior exerted by eEF1A2 was also described in BT549 human breast cancer cells (84) . In fact, filopodia formation in eEF1A2-expressing cells was dependent on the activity of PI3K, ROCK and Akt kinases.…”

The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration

“…In plants, EF1A1 acts as an activator of phosphatidylinositol 4-kinase (PI4K) and regulates phosphatidylinositol (4,5)-bisphosphate via its interaction with phospholipase Cγ1 (Yang et al, 1993;Yang and Boss, 1994). Recently, EF1A1 was identified as a binding partner of Akt2 (Lau et al, 2006), whereas the other isoform EF1A2 was shown to bind and activate PI4K and Akt, depending on the intracellular abundance of phosphatidylinositol (3,4,5)-trisphosphate (Amiri et al, 2006;Jeganathan and Lee, 2007). In this regard, DLC1 is also a target for Akt kinase signaling in response to insulin (Hers et al, 2006).…”

Translational Control in Tumour Progression and Drug Resistance

“…Moreover, downregulation of eEF1A2 expression leads to decreased expression of pAkt1 and to less extent of pAkt2 and promotes apoptosis [85]. Thus, eEF1A2 interaction with pAkt represents an important mechanism for the regulation of Akt-dependent survival signalling pathways in cancer [85,86].…”

“…In mouse fibroblast cell line NIH3T3, eEF1A2 interacts with peroxiredoxin-I (Prdx-I), resulting in increased activation of Akt, reduced activation of caspases 3 and 8, and protection against apoptotic death [84]. Moreover, downregulation of eEF1A2 expression leads to decreased expression of pAkt1 and to less extent of pAkt2 and promotes apoptosis [85]. Thus, eEF1A2 interaction with pAkt represents an important mechanism for the regulation of Akt-dependent survival signalling pathways in cancer [85,86].…”