Acyl-protein thioesterase 2 (APT2) (APT2)

Acyl-protein thioesterase 2 (APT2), also known as Lysophospholipase 2 (LYPLA2), is a cytosolic serine hydrolase that plays a pivotal role in the regulation of protein S-palmitoylation. It catalyzes the removal of long-chain fatty acids, such as palmitate, from cysteine residues on various signaling proteins, including HRAS, NRAS, and GAP43. This depalmitoylation activity is a key component of the palmitoylation cycle, which governs the spatial distribution and membrane trafficking of peripheral membrane proteins between the plasma membrane and endomembranes. Beyond its role in protein deacylation, APT2 also functions as a lysophospholipase and a prostaglandin glycerol ester hydrolase, contributing to broader lipid metabolism and signaling. In a therapeutic context, APT2 is primarily investigated as a target for RAS-driven cancers, where its inhibition disrupts the steady-state localization of oncogenic RAS isoforms and attenuates downstream signaling. Selective small-molecule inhibitors like ML349 have been developed as chemical probes to study its function and therapeutic potential. However, the high structural similarity between APT2 and its isoform APT1 presents significant challenges for achieving selectivity, and the broad role of depalmitoylation in cellular homeostasis raises concerns regarding potential systemic toxicity.

Other names

Lysophospholipase 2LYPLA2Lysophospholipase IILPL-IIPalmitoyl-protein hydrolase

Inhibition of protein depalmitoylation, leading to the mislocalization of S-acylated signaling proteins and disruption of oncogenic signaling pathways.