ENPP2

Official Full Name

ectonucleotide pyrophosphatase/phosphodiesterase 2

Organism

Homo sapiens

GeneID

5168

Background

The protein encoded by this gene functions as both a phosphodiesterase, which cleaves phosphodiester bonds at the 5' end of oligonucleotides, and a phospholipase, which catalyzes production of lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells and has angiogenic properties, and its expression is upregulated in several kinds of carcinomas. The gene product is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2008]

Synonyms

ATX; NPP2; ATX-X; PDNP2; LysoPLD; AUTOTAXIN; PD-IALPHA;

Bio Chemical Class

Phosphoric diester hydrolase

Protein Sequence

MARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEGWEEGPPTVLSDSPWTNISGSCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEENACHCSEDCLARGDCCTNYQVVCKGESHWVDDDCEEIKAAECPAGFVRPPLIIFSVDGFRASYMKKGSKVMPNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGNSMYDPVFDATFHLRGREKFNHRWWGGQPLWITATKQGVKAGTFFWSVVIPHERRILTILQWLTLPDHERPSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLKLHRCVNVIFVGDHGMEDVTCDRTEFLSNYLTNVDDITLVPGTLGRIRSKFSNNAKYDPKAIIANLTCKKPDQHFKPYLKQHLPKRLHYANNRRIEDIHLLVERRWHVARKPLDVYKKPSGKCFFQGDHGFDNKVNSMQTVFVGYGSTFKYKTKVPPFENIELYNVMCDLLGLKPAPNNGTHGSLNHLLRTNTFRPTMPEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPKNKLDELNKRLHTKGSTEERHLLYGRPAVLYRTRYDILYHTDFESGYSEIFLMPLWTSYTVSKQAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYDAFLVTNMVPMYPAFKRVWNYFQRVLVKKYASERNGVNVISGPIFDYDYDGLHDTEDKIKQYVEGSSIPVPTHYYSIITSCLDFTQPADKCDGPLSVSSFILPHRPDNEESCNSSEDESKWVEELMKMHTARVRDIEHLTSLDFFRKTSRSYPEILTLKTYLHTYESEI

Open

Disease

Fibrosis, Idiopathic interstitial pneumonitis, Pain, Postoperative inflammation, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) gene encodes a multifunctional protein endowed with both phosphodiesterase and phospholipase activities. The core function of this protein lies in hydrolyzing extracellular lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA), a signaling molecule. LPA is a critical cellular signal that can induce cell proliferation, chemotactic responses, and various biological functions associated with tumor cell migration and angiogenesis. This versatile enzyme is not only crucial for fundamental physiological processes but also participates in numerous pathological changes.

The product of the ENPP2 gene is primarily secreted and subsequently processed into its biologically active form. Its mRNA is highly expressed in adipose tissue, brain, spinal cord, testes, and ovaries under normal conditions and also detectable in the lungs, kidneys, and pancreas. ENPP2 expression is significantly raised in many malignancies and chronic inflammatory illnesses in disease states, therefore highlighting its essential function in pathogenic environments.

Evolution and Structural Characteristics of the ENPP Family

The ENPP family was first identified over 50 years ago, initially named NPP (Nucleotide Pyrophosphatases/Phosphodiesterases), and later renamed to ENPP to reflect its enzymatic characteristics and extracellular location. The family comprises seven members, ENPP1 to ENPP7. ENPP2, also known as Autotaxin (ATX), is the most representative member of this family and is recognized as a significant source of lysophospholipase D (lysoPLD) that catalyzes the formation of LPA from LPC.

All ENPP family members share a common phosphodiesterase (PDE) core domain, with structural and functional variations due to enzymatic properties and substrate preferences. For example, ENPP2's PDE domain is shorter by 18-20 amino acids compared to other family members, forming a unique hydrophobic pocket that confers its lysophospholipase activity. Additionally, the ENPP2 protein includes a somatomedin B (SMB) domain with integrin-binding capabilities, which may influence its activity and adhesion properties on the cell surface.

Figure 1 provides an overview of the structures and domain architecture of ENPP1-7, highlighting the multidomain ENPP1-3 and single-domain ENPP4-7 subgroups, with specific surface models and domain locations in sequence, created using UCSF ChimeraX and Blender. Figure 1. Overview of ENPP1–7 structures and domain architecture. (Borza R, et al., 2022)

Role of the ENPP2 Gene in Disease

Abnormal expression of the ENPP2 gene is closely associated with the onset and progression of various diseases. In cancers, ENPP2 expression is typically significantly elevated, and its chromosomal locus at 8q24 often exhibits somatic copy number increases or other genetic variants. For ovarian, breast, liver, and lung tumors, for example, gene amplification rates of ENPP2 reach 33%, 20%, 20%, and 11% respectively. Furthermore, under control by epigenetic changes including histone deacetylation inhibition and promoter hypermethylation is ENPP2 expression.

With its LPA generation fostering tumor cell proliferation, migration, and invasion via autocrine or paracrine pathways, ENPP2 operates in malignancies via several different mechanisms. LPA also induces neovascularization in endothelial cells, ensuring ample nutrient supply for tumor growth. In breast cancer, the ATX/LPA axis is closely linked to peritumoral adipose tissue, indicating that this paracrine signaling may play a crucial role in the tumor microenvironment.

ENPP2 in Chronic Inflammation and Fibrosis

Beyond cancer, ENPP2 and its produced LPA play a role in fibrosis and pathogenesis of chronic inflammatory disorders. ENPP2 released by synovial fibroblasts stimulates cytoskeletal rearrangement, proliferation, and migration through autocrine pathways in rheumatoid arthritis, hence aggravating inflammation. Damage-activated hepatocytes' released ENPP2 stimulates hepatic stellate cells and increases pro-fibrotic signaling in liver fibrosis. ENPP2 also plays a significant role in kidney and skin fibrosis.

ENPP2 and Neurological Disorders

ENPP2 is also significant in the nervous system. Highly expressed in the brain, its brain-specific isoform, ATXγ, has been linked in studies to development of neuropathic pain, myelination, and neuronal differentiation along the ENPP2/LPA axis. In neuroinflammative diseases including multiple sclerosis, ENPP2 and LPA levels are much raised in patient serum and cerebrospinal fluid. In experimental autoimmune encephalomyelitis, pharmacological studies show that blocking ENPP2 activity can reduce symptoms, therefore supporting its function in neurological disorders.

Application Prospects and Research Directions for ENPP2

Due to ENPP2's critical role in various diseases, it has become a key target in drug development. Targeting ENPP2 activity with small molecule inhibitors can effectively reduce LPA levels, thereby alleviating inflammation, inhibiting tumor growth, and improving the course of fibrotic diseases. ENPP2's potential in diagnostics, particularly in early detection of tumors and chronic inflammatory diseases, is also noteworthy.

Future research may focus on several areas: firstly, further elucidating the three-dimensional structure of ENPP2 and its interactions with substrates or inhibitors; secondly, exploring its functions in other less studied diseases; thirdly, developing more efficient targeted drugs and diagnostic tools. By deeply investigating the functional mechanisms of the ENPP2 gene in pathological processes, new strategies and breakthrough advancements for treating major diseases are expected.

References:

Borza R, Salgado-Polo F, et al. Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity. J Biol Chem. 2022 Feb;298(2):101526.
Cholia RP, Nayyar H, et al. Understanding the Multifaceted Role of Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) and its Altered Behaviour in Human Diseases. Curr Mol Med. 2015;15(10):932-43.
Ninou I, Magkrioti C, et al. Autotaxin in Pathophysiology and Pulmonary Fibrosis. Front Med (Lausanne). 2018 Jun 13;5:180.

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