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Differential Regulation of Src Family Kinases by HIV‐1 Nef

The HIV‐1 virulence factor, Nef, promotes viral pathogenicity by altering host cell signaling pathways. Nef is known to bind several members of the Src kinase family, implicating these non‐receptor protein‐tyrosine kinases in the pathogenesis of HIV/AIDS. However, the direct effect of Nef binding on Src family kinase (SFK) activity has not been systematically investigated. We explored this issue using S. cerevisiae, a well‐defined system for the study of SFK regulation. Previous studies have shown that ectopic expression of c‐Src arrests yeast cell growth in a kinase‐dependent manner. We expressed Fgr, Fyn, Hck, Lck, Lyn, and Yes as well as c‐Src in yeast and found that each kinase was active and induced growth suppression. Co‐expression of the negative regulatory kinase Csk reversed the growth‐inhibitory effect. We then co‐expressed each SFK with HIV‐1 Nef in the presence of Csk. Nef strongly activated Hck, Lyn, and Src, partially activated Fgr, but did not affect Fyn, Lck, or Yes. Mutagenesis of the Nef PxxP motif essential for SH3 binding greatly reduced the effect of Nef on Hck, Lyn, and Src, suggesting that SFK SH3 domain engagement and linker displacement is a common feature of Nef‐induced SFK activation. Our data show that Nef selectively activates Hck, Lyn and Src among SFKs, identifying these kinases as mediators of Nef signaling and as potential targets for anti‐HIV drug discovery.