CREB3 is cleaved by regulated intramembrane proteolysis (RIP) (Raggo et al. 2002, Liang et al. 2006, Eleveld-Trancikova et al. 2010). As inferred from other RIP susbsrates, MBTPS2 (S2P) is believed to cleave CREB3 after MBTPS1 (S1P) cleaves (Raggo et al. 2002). Based on homology with cleavage sites in SREBP (SREBF) homologues, the cleavage site in CREB3 is estimated to be at about amino acid 254 at the cytoplasmic face of the transmembrane domain (Raggo et al. 2002).