p21-activated kinase 1 plays a critical role in cellular activation by Nef

The activation of Nef-associated kinase (NAK) by Nef from human and simian immunodeficiency viruses is critical for efficient viral replication and pa thogenesis. This induction occurs via the guanine nucleotide exchange facto r Vav and the small GTPases Rac1 and Cdc42. In this study, we identified NA K as p21-activated kinase 1 (PAK1). PAK1 bound to Nef in vitro and in vivo. Moreover, the induction of cytoskeletal rearrangements such as the formati on of trichopodia, the activation of Jun N-terminal kinase, and the increas e of viral production were blocked by an inhibitory peptide that targets th e kinase activity of PAK1 (PAK1 83-149). These results identify NAK as PAK1 and emphasize the central role its kinase activity plays in cytoskeletal r earrangements and cellular signaling by Nef.