Protein-serine O-palmitoleyltransferase porcupine (PORCN)

Protein-serine O-palmitoleyltransferase porcupine (PORCN) is an endoplasmic reticulum-resident enzyme belonging to the membrane-bound O-acyltransferase (MBOAT) family [1]. Its primary biological role is the post-translational palmitoylation of Wnt proteins, a process essential for their proper folding, secretion, and binding to Frizzled receptors [1, 3]. Because Wnt signaling is a critical driver of cell proliferation and stem cell maintenance, dysregulation of PORCN-mediated Wnt secretion is implicated in various malignancies, particularly those with RNF43 mutations or RSPO fusions [3]. In the context of drug development, PORCN inhibitors like LGK974 and RXC004 are being investigated as a means to block the secretion of all Wnt ligands, thereby suppressing Wnt-driven tumor growth [2]. However, since Wnt signaling is also vital for normal tissue homeostasis, particularly in the bone and gut, therapeutic use of PORCN inhibitors faces challenges related to bone density loss and gastrointestinal side effects [3]. Additionally, loss-of-function mutations in the PORCN gene are the cause of focal dermal hypoplasia, a multi-system developmental disorder [4]. Sources: [1] UniProt (Q9H237); [2] PubMed (PMID: 23047551); [3] PubMed (PMID: 28814674); [4] NIH/GARD.

Other names

Porcupine homologPORCMG61DHOFPPNMembrane-bound O-acyltransferase porcupine

PORCN inhibitors bind to the enzyme's active site, preventing the transfer of a palmitoleoyl group to a conserved serine residue on Wnt proteins, which effectively halts Wnt secretion and downstream signaling [2, 3].