Disease relevance of ENPP2

• Autotaxin, also known as ENPP2, was originally isolated from the culture medium of melanoma cells as a cell-motility promoting protein [1].
• In this study, we found that ATX is highly expressed in glioblastoma multiforme (GBM), the most malignant glioma due to its high infiltration into the normal brain parenchyma, but not in tissues from other brain tumors [2].
• Transcriptional over-expression of ENPP2 gene was endogenously silenced by using RNA interference technique, and then recapitulated corresponding molecular changes in MDA435 breast cancer cells [3].
• Here we show that EBV infection of Hodgkin lymphoma cells results in the induction of autotaxin, a secreted tumor-associated factor with lysophospholipase-D activity [4].
• Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells [4].

Psychiatry related information on ENPP2

• Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients [5].

High impact information on ENPP2

• Autotaxin (ATX) is a tumor cell motility-stimulating factor, originally isolated from melanoma cell supernatants [6].
• Moreover, we demonstrate that several cancer cell lines release significant amounts of LPC, a substrate for ATX, into the culture medium [6].
• The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine production of LPA contributes to tumor cell motility, survival, and proliferation [6].
• The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate [6].
• Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines [6].

Chemical compound and disease context of ENPP2

• Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid [2].
• Our results identify the induction of autotaxin and the subsequent generation of LPA as key molecular events that mediate the EBV-induced growth and survival of Hodgkin lymphoma cells and suggest that this pathway may provide opportunities for novel therapeutic intervention [4].
• ATX is a 125-kDa glycoprotein, previously isolated from a human melanoma cell line (A2058), which elicits chemotactic and chemokinetic responses at picomolar to nanomolar concentrations [7].
• Finally, when melanoma cells are treated with inhibitors of carbohydrate processing, such as N-methyl-1-deoxynojirimycin, 1-deoxymannojirimycin and swainsonine, they still secrete a motility-stimulating autotaxin [8].
• Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis [9].

Biological context of ENPP2

• Finally, we show by electrophoretic mobility shift assays that two consensus NFAT binding sites found in the autotaxin promoter strongly and specifically bind NFAT1 from integrin alpha6beta4 expressing cells [10].
• We further demonstrate that increased autotaxin secretion from integrin alpha6beta4 expressing cells acts to enhance chemotaxis through its ability to convert lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and accounts for 80% of the motogenic activity of the conditioned medium [10].
• In summary, we find that the alpha6beta4 integrin potentiates autotaxin expression through the upregulation and activation of NFAT1 [10].
• Application of nonparametric Wilcoxon statistical analyses (P<0.05) and the selection criteria of 2-fold differential gene expression change resulted in the identification of 368 genes including 133 up-regulated and 235 genes under-expressed in ENPP2-silencing MDA435 cells [3].
• Up-regulation of autotaxin increased the generation of lysophosphatidic acid (LPA) and led to the enhanced growth and survival of Hodgkin lymphoma cells, whereas specific down-regulation of autotaxin decreased LPA levels and reduced cell growth and viability [4].

Anatomical context of ENPP2

• Similarly, mixing purified ATX into the Matrigel resulted in new blood vessel formation within the plug, similar to that produced by vascular endothelial growth factor [11].
• Mechanistically, ATX is not a strong chemoattractant for human endothelial cells (HUVECs); however, it strongly stimulates motility in human coronary artery smooth muscle cells [11].
• A human cDNA clone encoding autotaxin, a tumor cell motility-stimulating protein, reveals that this protein is an ecto/exo-enzyme with significant homology to the plasma cell membrane differentiation antigen PC-1 [7].
• Data base analysis of the ATX sequence revealed a 45% amino acid identity (including 30 out of 33 cysteines) with PC-1, a pyrophosphatase/type I phosphodiesterase expressed on the surface of activated B cells and plasma cells [7].
• In cultured allantois explants, neither ATX nor LPA was angiogenic [12].

Associations of ENPP2 with chemical compounds

• Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells [10].
• ATX is identical to lysophospholipase D, which produces a bioactive phospholipid, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC) [2].
• Moreover, we identified deregulated genes in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT [13].
• ATX binds ATP and is phosphorylated only on threonine [14].
• Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate [15].

Physical interactions of ENPP2

• The 5' region of the human PDNP2 gene contains four putative binding sites of transcription factor Sp1 without typical TATA or CAAT boxes, and there is a potential octamer binding motif in intron 2 [16].

Enzymatic interactions of ENPP2

• N-terminal sequencing of the secreted autotaxin revealed that it was cleaved at two N-terminal sites that match the consensus sequences for cleavage by a signal peptidase and furin [1].

Regulatory relationships of ENPP2

• In HUVECs, ATX expression is up-regulated by basic fibroblast growth factor in a time-dependent manner [11].
• Pretreatment of the melanoma cells with pertussis toxin abolishes the response to purified ATX, indicating that ATX stimulates motility through a receptor acting via a pertussis toxin-sensitive G protein [17].
• Collectively, these data strongly suggest autotaxin induces uPA expression via the Gi-PI3K-Akt-NF-kappaB signaling pathway that might be critical for autotaxin-induced tumor cell invasion and metastasis [18].
• Autotaxin stimulates urokinase-type plasminogen activator expression through phosphoinositide 3-kinase-Akt-necrosis factor kappa B signaling cascade in human melanoma cells [18].

Other interactions of ENPP2

• One of the glioblastomas that showed the highest ATX expression (SNB-78), as well as ATX-stable transfectants, showed LPA1-dependent cell migration in response to LPA in both Boyden chamber and wound healing assays [2].
• One down-regulated gene product, secreted autotaxin/lyso-phospholipase D, was of particular interest because its down-regulation by CST6 could explain most of CST6's effect on the breast cancer cells [19].
• Tenocytes (TSC and TIF) expressed ecto-nucleotidase mRNA (ENTPD3 and ENPP1, ENPP2) [20].
• In addition, ATX stimulates HUVECs grown on Matrigel to form tubules, much like vascular endothelial growth factor [11].
• Utilizing polymerase chain reaction screening of the CEPH YAC library, we localized the autotaxin gene to human chromosome 8q23-24 [21].

Analytical, diagnostic and therapeutic context of ENPP2

• In our current study, we show that expression of the alpha6beta4 integrin in MDA-MB-435 breast carcinoma cells leads to increased expression of the autocrine motility factor autotaxin, as determined by Affymetrix gene chip, real-time quantitative RT-PCR and immunoblot analyses [10].
• Quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed differential expression of ENPP2/autotoxin and six other genes between PZ versus CA, as well as differential expression of six genes between BPH versus CA [22].
• Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein [17].
• 2. Purified ATX was digested with cyanogen bromide and trypsin, and the resulting ATX peptides were purified by reverse-phase high performance liquid chromatography [17].
• Homogeneity of ATX was verified by two-dimensional gel electrophoresis [17].

References