Fig. 2

SCAP N-glycosylation is essential for SREBP trafficking and activation. SREBP activation is repressed by the ER-resident protein Insig, which binds to SCAP to prevent SREBP translocation and nuclear activation. The Nobel Prize-winning laboratories of Brown and Goldstein revealed that sterols modulate Insig interaction with SCAP to retain the SCAP/SREBP complex in the ER and inhibit SREBP [273, 274]. Our recent work has shown that glucose-mediated N-glycosylation stabilizes SCAP and promotes its dissociation from Insig, triggering the trafficking of the SCAP/SREBP complex from the ER to the Golgi, where SREBPs are cleaved to release their transcriptionally active N-terminal fragments to activate lipogenesis for tumor growth [55]. We further showed that EGFR signaling enhances glucose intake and thereby promotes SCAP N-glycosylation and SREBP activation