Abstract
Human dynactin-associated protein (dynAP) is a transmembrane protein that promotes AktSer473 phosphorylation. Here, we report the oncogenic properties of dynAP. In contrast to control NIH3T3 cells expressing LacZ (NIH3T3LacZ), NIH3T3dynAP cells vigorously formed foci in two-dimensional culture, colonies on soft agar, and spheroids in anchorage-deficient three-dimensional culture. NIH3T3dynAP cells injected into nude mice produced tumors with abundant blood vessels and weak cell—cell contacts. Expression of dynAP elevated the level of rictor (an essential subunit of mTORC2) and promoted phosphorylation of FOXO3aSer253. FOXO3a is a transcriptional factor that stimulates expression of pro-apoptotic genes and phosphorylation of FOXO3a abrogates its function, resulting in promoted cell survival. Knockdown of rictor in NIH3T3dynAP cells reduced AktSer473 phosphorylation and formation of foci, colony in soft agar and spheroid, indicating that dynAP-induced activation of the mTORC2/AktSer473 pathway for cell survival contributes to cell transformation. E-cadherin and its mRNA were markedly reduced upon expression of dynAP, giving rise to cells with higher motility, which may be responsible for the weak cell-cell adhesion in tumors. Thus, dynAP could be a new oncoprotein and a target for cancer therapy.
Highlights
The PI3K-Akt-mammalian target of rapamycin complex signaling pathway plays critical roles in the regulation of a wide range of cellular processes including growth, proliferation, and survival [1,2,3,4,5,6]
A major 42 kDa component and a minor 20 kDa component were detected in NIH3T3dynAP cells but not in control NIH3T3LacZ cells
Morphological differences were not found among parental NIH3T3, NIH3T3LacZ and NIH3T3dynAP cells
Summary
The PI3K-Akt-mammalian (officially mechanistic) target of rapamycin complex (mTORC) signaling pathway plays critical roles in the regulation of a wide range of cellular processes including growth, proliferation, and survival [1,2,3,4,5,6]. Deregulated activation of this pathway has been implicated in a number of pathological conditions including cancer [6]. Akt phosphorylated at Ser473 acquires the capability to phosphorylate additional substrates including FOXO transcriptional factors that promote expression of pro-apoptotic genes [9, 10]. Phosphorylation of FOXO proteins inhibits their nuclear translocation, thereby supporting cell survival
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