Tellier et al., 2007). Notably, in addition to activation, TNF was also found to induce relocalization of nSMase2 to the PM in A549 lung epithelial cells and this was also dependent on p38 MAPK as well as requiring PKC-delta (Clarke et al., 2008; Clarke et al., 2007; Tellier et al., 2007). FAN (factor associated with N-SMase activation) has been identified as an adapter protein that associates with the TNF receptor and plays a role in activating N-SMase (Adam-Klages et al., 1996). More recently, the polycomb group protein EED was found to interact with both nSMase2 and RACK1(Philipp et al., 2010), an interaction partner of FAN (Tcherkasowa et al., 2002). Furthermore, the TNF-dependent activation of nSMase2 is completely abrogated by inhibition of EED. Thus, TNF induces formation of a TNF receptor-FAN-RACK1-EED complex at the PM resulting in activation of nSMase2. Taken together, these data confirm nSMase2 as a TNF-α-responsive enzyme.
