Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP is a protein that in humans is encoded by the SCAP gene. SCAP contains a sterol-sensing domain and seven WD domains.
Ammonia activates the dissociation of glucose-regulated, N-glycosylated SREBP-cleavage-activating protein (SCAP) from insulin-inducible gene protein (Insig), an endoplasmic reticulum-retention protein, leading to SREBP translocation and lipogenic gene expression. Notably, 25-hydroxycholesterol blocks ammonia to access its binding site on SCAP. Mutating aspartate D428 to alanine prevents ammonia binding to SCAP, abolishes SREBP-1 activation, and suppresses tumor growth. The study of Cheng et al. characterizes the unknown role, opposite to sterols, of ammonia as a key activator that stimulates SCAP-Insig dissociation and SREBP-1 activation to promote tumor growth and demonstrates that SCAP is a critical sensor of glutamine, glucose, and sterol levels to precisely control lipid synthesis 1).