Find CERK Products Interaction Network for CERK CERK Details

Related Pathways Ceramide Signaling Glycerolipid Metabolism Sphingolipid Metabolism View All Pathways

Synonyms: AI848610, CERK, Cerk predicted, D330016D08Rik, dA59H18.2, dA59H18.3, DKFZp434E0211, FLJ21430, FLJ23239, hCERK, KIAA1646, LK4, MGC131878, mKIAA1646

Ceramide Pathway

The sphingolipid, ceramide, a second messenger activated through the tumor necrosis factor (TNF) receptor, is a mediator of pro-apoptotic events. It is produced by two distinct, membrane-associated neutral (N-SMase) and an endosomal acidic (A-SMase), sphingomyelinases which cleave sphingomyelin. These SMases are activated through binding to the 55 kDa TNF receptor (TNF-R55) via different domains. Downstream signaling by ceramide is dependent upon which SMase produces it. A-SMase is activated through TNF-receptor associated pro-apoptotic proteins TRADD and FADD associated with the death domain (DD). Ceramide promotes apoptosis via several mechanisms.

Ceramide can activate phosphatases such as protein phosphatase I (PP1) and protein phosphatase 2A (PP2A). These phosphatases can inactivate survival signaling molecules such as classical and novel PKC isoforms and Akt/PKB. They can also activate pro-apoptotic factors such as BAD and BAX. Ceramide signals activation of the Ras (KSR)/ceramide-activated protein kinase (CAPK), Ras, c-Raf-1, MEK1, ERK pathway. This pathway is pro-growth but it becomes pro-apoptotic in the presence of dephosphorylated BAD. Direct interaction of ceramide with pre-pro cathepsin D results in autocatalytic proteolysis and formation of cathepsin D. Cathepsin D has been linked to mitochondrial apoptosis through cleavage of BiD. Ceramide promotes activation of PKCzeta by phosphorylation, which in turn promotes NFkappaB mediated cell survival. However, when PAR-4 (prostate apoptosis response-4) is also present it promotes apoptosis. Ceramide-1-phosphate (Sph-1-P) blocks apoptosis by inhibiting acidic sphingomyleinase.