Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway

de Vries, Erik; Tscherne, Donna M.; Wienholts, Marleen J.; Cobos-Jiménez, Viviana; Scholte, Florine; García-Sastre, Adolfo; Rottier, Peter J. M.; de Haan, Cornelis A. M.

In agreement with our observation that the DYNA-IND entry of IAV was inhibited by PP2, an inhibitor of src family kinases, the non-receptor tyrosine kinase c-src has been shown to function as a key signaling intermediate in the induction of macropinocytosis via a mechanism independent of Rac1 or cdc42 [49] [50] [51] . Downstream effects of c-src on actin networks proceed, amongst others, via phosphorylation of cortactin by c-src resulting in accelerated macropinosome formation [50] . C-src has been shown to associate with macropinosomes [49, 51] , both during their formation and their trafficking, while c-src kinase activity is required for macropinocytosis following EGF stimulation of HeLa cells [49] . Interaction of HSP90 with c-src was recently shown to induce c-src kinase activity [54] . Also HSP90 has been demonstrated to associate with macropinosomes, while its specific inhibitor geldanamycin reduced the membrane ruffling that preceded macropinocytosis [66] . Thus, the inhibition of IAV entry via macropinocytosis by AA-geldanamcyin may very well involve the effects of HSP90 on c-src.