The nonreceptor tyrosine kinase Src is involved in multiple signal transduction pathways that control proliferation and differentiation. Its activity is tightly controlled by intramolecular interactions that involve its Src-homology (SH) domains. Several proteins upregulate Src activity by disrupting these interactions but few proteins are known to downregulate Src activity. Now, on , Zohra Rahmani identifies APRO4 as a negative regulator of Src-mediated signalling. Rahmani shows that APRO4 - a member of an `antiproliferative gene' family - interacts with the Src SH2 and SH3 domains through its C-terminal proline-rich domain and downregulates Src kinase activity in vitro. In addition, the author shows that overexpression of APRO4 in PC12 cells inhibits neurite formation and Ras/MAP kinase signalling; by contrast, antisense-RNA-mediated downregulation of endogenous APRO4 expression induces Src activation and spontaneous neurite formation. Finally, Rahmani observes that, in PC12 cells stimulated to form neurites by treatment with FGF, the kinetics of endogenous Src inactivation correlate with increased co-immunoprecipitation with APRO4. Thus, Rahmani concludes, APRO4 plays an important role in the negative regulation of Src signalling by controlling the basal threshold for Src activation.
