ENPP2

ENPP2, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 or autotaxin (ATX), is a secreted enzyme in the ENPP family. It possesses lysophospholipase D activity and converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) in the extracellular space. The reaction requires divalent cations such as Mg2+ or Ca2+. ENPP2 is widely expressed and circulates in serum and other body fluids, where it serves as a major source of extracellular LPA signaling.

LPA, the product of ENPP2 activity, signals through multiple G protein-coupled receptors (LPAR1-6) to regulate processes including cell proliferation, migration, survival, angiogenesis, and cytoskeletal organization. Through these pathways, ENPP2 participates in development and wound healing and contributes to pathological conditions. In cancer, elevated ENPP2/LPA signaling can promote tumor cell motility, invasion, and metastasis and is associated with poorer prognosis in several cancer types. In fibrosis and chronic inflammatory diseases, LPA signaling driven by ENPP2 promotes fibroblast activation and tissue remodeling.

Regulation of ENPP2 occurs at transcriptional and post-translational levels, with secretion by a variety of cells such as tumor cells, endothelial cells, and adipocytes. Its activity can be influenced by extracellular inhibitors and glycosylation, among other factors.

Therapeutically, ENPP2 is a target of interest. Small-molecule autotaxin inhibitors aim to reduce LPA production and downstream signaling, and have been explored in preclinical models and clinical trials for fibrotic diseases and cancer. ENPP2 expression and LPA signaling are also studied as potential biomarkers for prognosis and treatment response.