FIG. 6.

Differential role for endocytosis in receptor-dependent Nox1 generation of ROS and activation of cellular signalling. In vascular SMC, TNF-α induces a Nox1-dependent, dynamin-dependent, endosomal generation of ROS with subsequent activation of PI3K-Akt-ATF-1 pathway. In contrast, thrombin activates Nox1 to transactivate the EGFR via metalloproteinase (MP)-mediated shedding of EGF-like ligands, with subsequent amplification of dynamin-independent ROS generation. Activation of PI3K-Akt-ATF-1 by thrombin is inhibited by dn-dynamin, consistent with its dependence on internalization of the activated EGFR. Internalization of receptor complexes is important in the temporal regulation of signaling.