ENPP-2, also known as Autotaxin, is a member of the ectonucleotide pyrophosphatase/phosphodiesterase （NPP） family and a secreted enzyme encoded by the ENPP2 gene. It shares 40-50% sequence identity with ENPP-1 and ENPP-3 and contains an N-terminal intracellular domain, a single transmembrane domain, and a large extracellular domain that includes a catalytic domain, two somatomedin B-like domains, and a C-terminal nuclease-like domain.
Unlike ENPP-1 and ENPP-3, ENPP-2 has weak nucleotide activity but exhibits lysophospholipase D activity, converting lysophosphatidylcholine to lysophosphatidic acid （LPA） and choline. It can also hydrolyze sphingosylphosphorylcholine to produce sphingosine-1-phosphate （S1P）. Both LPA and S1P inhibit ENPP-2 activity.
Originally identified for its role in stimulating tumor cell motility, ENPP-2 enhances tumor invasion and metastasis and is upregulated in carcinomas such as breast and lung cancer. It is highly expressed in the brain and adipose tissue. Recombinant mouse ENPP-2, lacking transmembrane and intracellular domains, is secreted. ENPP-2's role in generating LPA is crucial for cell processes like proliferation, migration, and aggregation.
Its upregulation in cancer and correlation with tumor invasiveness make ENPP-2 a promising target for anti-cancer therapies. Additionally, increased serum ENPP-2 activity is linked to hepatic fibrosis in chronic liver disease due to hepatitis C virus infection.