UCSF

Early adenoviral proteins perturb the same pathways that are deregulated in cancer cells in order to drive viral replication. For example, E1A binds and inactivates the tumor suppressor pRb, while E1B-55K in conjunction with E4-ORF6 results in the degradation of p53. As a result, the studies of E1A and E1B have contributed greatly to our understanding of the Rb and p53 pathways, respectively. Other cellular pathways are also targeted by adenoviral proteins. Our lab has demonstrated that the early adenoviral protein E4-ORF1 potently activates PI3K alpha signaling. This activation is not through protein-protein interactions with PI3K enzymes, impinging on insulin signaling, disruption of Pten function, or activation of Ras family proteins. To determine how E4-ORF1 was activating the PI3K pathway, we used an unbiased proteomics approach to identify novel binding partners that played a role in PI3K signaling. We found the E4-ORF1 bound to a PDZ complex consisting of Cask, Mint1 and Veli-3 through another PDZ protein called Dlg1. Our results suggest that the Cask, Mint1, and Veli-3 complex acts as a repressor for PI3K signaling by both E4-ORF1 and growth factors, whereas Dlg1 is required for activation. E4-ORF1 and growth factors through an unknown cellular factor may be mislocalizing the repressor complex using Dlg1, which allows PI3K signaling to occur. Thus, the role of Dlg1, Cask, Mint1, and Veli-3 represents a novel regulatory step in this critical signaling pathway.