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ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2)

Written2007-02Mary L. Stracke, Timothy Clair
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 2A33, MSC 1500, 9000 Rockville Pike, Bethesda, MD 20892

(Note : for Links provided by Atlas : click)


Alias (NCBI)Autotaxin
PD1 alpha
lysophospholipase D
HGNC Alias symbATX
HGNC Alias nameautotaxin
HGNC Previous namePDNP2
LocusID (NCBI) 5168
Atlas_Id 40455
Location 8q24.12  [Link to chromosome band 8q24]
Location_base_pair Starts at 119557086 and ends at 119638839 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ENPP2.png]
Local_order Telomeric to (nephroblastoma overxpressed gene), centromeric to TAF2; colocalized with pseudogene CYCSP23.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
AUTS2 (7q11.22)::ENPP2 (8q24.12)DEPTOR (8q24.12)::ENPP2 (8q24.12)ENPP2 (8q24.12)::ETNK1 (12p12.1)
ENPP2 (8q24.12)::EXOC3-AS1 (5p15.33)ENPP2 (8q24.12)::MALAT1 (11q13.1)HSD17B3 (9q22.32)::ENPP2 (8q24.12)
PLEC (8q24.3)::ENPP2 (8q24.12)TBL1XR1 (3q26.32)::ENPP2 (8q24.12)


Note mRNA length 3276 or 3120 bp, depending upon alternate splicing.
  ENPP2 Gene: Intron-exon organization of ENPP2.
Description The ENPP2 gene is 81,754 bp in length and is composed of 26 exons. Part of exon 1 and 26 are untranslated (UTR); translation extends from the remainder of exon 1 through the proximal portion of exon 26; however, there is a 152 bp exon (exon 12) that is alternatively spliced and is included primarily in neurally derived tissues.
Transcription The mRNA for ENPP2 is 3276 bp with exon 12 and 3120 bp without it. The ENPP2 promoter is reported to have four SP1 sites as well as binding sites for NFAT and NF-kappaB but no TATA or CAAT boxes. The only transcription factor that has been proven to increase ENPP2 protein expression is NFATC2/NFAT1, after release of alpha6beta4 from hemidesmosomes in a breast cancer cell line. A number of growth factors have been found to stimulate ENPP2 protein expression, while several inflammatory cytokines have been reported to inhibit expression.
Pseudogene CYCSP23


  ENPP2 Protein (NPP2/ATX): Organization of domains and other critical elements within ENPP2.
Description The ENPP2 protein, NPP2 or ATX, is an N-glycolsylated member of the ecto-nucleotide pyrophosphatase and phosphodiesterase (NPP) family of proteins. The NPP2 precursor contains 915 amino acids, 105.2 KDa; and an alternately spliced variant is 863 amino acids, 99.0 KDa. The amino terminal signal peptide sequence is cleaved at a signal peptidase site between G27 and F28 to yield a secreted protein that contains 888/836 amino acids, 102.3/96.9 KDa. NPP2 contains up to 3 ASN-linked glycosylation sites that appear to be required for secretion as well as for stabilization of its active conformation.
Expression NPP2 is expressed in many tissues during development, but it is critical for blood vessel maturation and neurogenesis. Certain inflammatory cytokines and the tumor suppressor CST6 downregulate ENPP2 expression, and some of the NPP2 products exert a negative feedback on its expression. Conversely, a number of growth factors as well as EBV infection (in Hodgkin's lymphoma) upregulate ENPP2 expression. Disruption of hemidesmosomes in breast cancer cells releases alpha6beta4, which initiates a signaling cascade that culminates in the activation of the transcription factor NFAT1, which binds to the ENPP2 promoter to upregulate protein expression. Upregulation of ENPP2 has been reported in a number of aggressive tumors, including glioblastoma, undifferentiated anaplastic thyroid carcinoma, invasive breast carcinoma, and metastatic hepatocellular carcinoma.
In adults, NPP2 is the major source of serum and plasma lysophospholipase D activity. It is also highly expressed in brain, kidney, liver, ovary, small intestine, and placenta, and is present in many other tissues.
Function NPP2 is a Type 2 nucleotide pyrophosphatase and phosphodiesterase that also has ATPase activity. In addition, NPP2 is the major source of serum and plasma lysophospholipase D activity, hydrolyzing lysophosphatidylcholine into lysophosphatidic acid as well as cyclic phosphatidic acid. NPP2 also hydrolyzes sphingosylphosphorylcholine into sphingosine-1-phosphate; however, NPP2 is not a major source of sphingosine-1-phosphate in plasma. The production of lysophosphatidic acid is thought to account for many of the physiological and pathological roles of ENPP2.
Both enzymatic activities of NPP2 share a common catalytic domain. Like other members of the NPP family, NPP2 is a metallo-enzyme with binding sites for 2 metal atoms coordinated by three critical histidines (H316, H360, and H475) and associated aspartates (D172, D312, and D359). T210 is nucleotidylated during the nucleotide pyrophosphatase/phosphodiesterase reaction and is essential for hydrolysis of substrate during the lysophospholipase D reaction as well.
Homology NPP2 is a member of the nucleotide pyrophosphatase and phosphodiesterase family, which includes ENPP1 (PC1) and ENPP3 (B10). Although the catalytic domain is highly conserved within this family of proteins, only NPP2 possesses lysophospholipase D activity.


Note There are a number of single nucleotide polymorphisms (SNPs) that have been reported within the ENPP2 gene but none are yet reported to be associated with altered phenotype. However, knockout of ENPP2 is lethal in mice (approximately E12), therefore mutations associated with loss of function might be lethal.

Implicated in

Entity Various cancers
Disease Overexpression of the ENPP2 protein has been associated with tumor cell motility and invasion, tumor growth and metastasis, and blood vessel formation.
Prognosis ENPP2 is over-expressed in poorly differentiated non-small cell lung carcinomas and invasive and metastatic hepatocellular carcinoma. In thyroid carcinomas, ENPP2 expression was found to be higher in undifferentiated anaplastic thyroid carcinoma cell lines and tissues than in follicular thyroid carcinomas or goiters. When glioblastoma multiforme cells were collected from tumor cores vs. areas of white matter invasion, ENPP2 was found to be overexpressed predominantly at the invasive front.
Oncogenesis Upregulation of NPP2 expression appears to be associated with cancer progression rather than with oncogenesis. Transfection of ENPP2 cDNA into mouse fibroblast cell lines (NIH3T3 clone7) did not result in tumorigenic cell lines, but transfection into Ras-transformed fibroblasts resulted in rapidly growing, hematogenous, highly metastatic tumors. NPP2 expression was found in Hodgkin's lymphoma cells as well as in . In the Hodgkin's lymphomas , EBV infection was correlated to induction of ENPP2 expression (P = 0.006).
Transfection of the tumor suppressor CST6 into MDA-MB-435 cells resulted in down-regulation of ENPP2. In contrast, down regulation of ENPP2 by specific siRNAs resulted in down-regulation of the tumor suppressors, thrombospondin-1 and thrombospondin-2 (THBS1 and THBS2, respectively).
Entity Diabetes
Disease NPP2 expression is highly upregulated during adipocyte differentiation and its product, lysophosphatidic acid, stimulates proliferation in preadipocytes. In genetically obese, diabetic mice, NPP2 expression was increased in adipose tissue compared to their lean siblings. This is a possible model for type 2 diabetes, which has a strong genetic component.


Developmental expression analysis of murine autotaxin (ATX).
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PMID 10473125
Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells.
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Blood. 2005 ; 106 (6) : 2138-2146.
PMID 15933052
Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun.
Black EJ, Clair T, Delrow J, Neiman P, Gillespie DA
Oncogene. 2004 ; 23 (13) : 2357-2366.
PMID 14691447
Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression.
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PMID 15700135
Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer.
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Journal of cellular biochemistry. 2004 ; 92 (5) : 900-912.
PMID 15258914
Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells.
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Oncogene. 2005 ; 24 (32) : 5125-5130.
PMID 15897878
Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate.
Clair T, Aoki J, Koh E, Bandle RW, Nam SW, Ptaszynska MM, Mills GB, Schiffmann E, Liotta LA, Stracke ML
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PMID 14500380
Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities.
Clair T, Lee HY, Liotta LA, Stracke ML
The Journal of biological chemistry. 1997 ; 272 (2) : 996-1001.
PMID 8995394
Footer: a quantitative comparative genomics method for efficient recognition of cis-regulatory elements.
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Genome research. 2005 ; 15 (6) : 840-847.
PMID 15930494
Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity.
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The Journal of biological chemistry. 2003 ; 278 (20) : 18162-18169.
PMID 12642576
Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination.
Fox MA, Colello RJ, Macklin WB, Fuss B
Molecular and cellular neurosciences. 2003 ; 23 (3) : 507-519.
PMID 12837632
The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site.
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FEBS letters. 2003 ; 538 (1-3) : 60-64.
PMID 12633853
Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1.
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The Journal of biological chemistry. 2004 ; 279 (17) : 17634-17639.
PMID 14744855
Expression and transcriptional regulation of the PD-Ialpha/autotaxin gene in neuroblastoma.
Kawagoe H, Stracke ML, Nakamura H, Sano K
Cancer research. 1997 ; 57 (12) : 2516-2521.
PMID 9192834
Expression, regulation and function of autotaxin in thyroid carcinomas.
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PMID 15027116
Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities.
Koh E, Clair T, Woodhouse EC, Schiffmann E, Liotta L, Stracke M
Cancer research. 2003 ; 63 (9) : 2042-2045.
PMID 12727817
The N-terminal hydrophobic sequence of autotaxin (ENPP2) functions as a signal peptide.
Koike S, Keino-Masu K, Ohto T, Masu M
Genes to cells : devoted to molecular & cellular mechanisms. 2006 ; 11 (2) : 133-142.
PMID 16436050
Autotaxin promotes motility via G protein-coupled phosphoinositide 3-kinase gamma in human melanoma cells.
Lee HY, Bae GU, Jung ID, Lee JS, Kim YK, Noh SH, Stracke ML, Park CG, Lee HW, Han JW
FEBS letters. 2002 ; 515 (1-3) : 137-140.
PMID 11943209
Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin.
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The Journal of biological chemistry. 1996 ; 271 (40) : 24408-24412.
PMID 8798697
Cloning, chromosomal localization, and tissue expression of autotaxin from human teratocarcinoma cells.
Lee HY, Murata J, Clair T, Polymeropoulos MH, Torres R, Manrow RE, Liotta LA, Stracke ML
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PMID 8579579
Autotaxin stimulates urokinase-type plasminogen activator expression through phosphoinositide 3-kinase-Akt-nuclear [corrected] factor kappa B signaling cascade in human melanoma cells.
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Melanoma research. 2006 ; 16 (5) : 445-452.
PMID 17013094
cDNA cloning of the human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases.
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PMID 7982964
Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor.
Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, Stracke ML
Cancer research. 2001 ; 61 (18) : 6938-6944.
PMID 11559573
Identification of large-scale molecular changes of Autotaxin(ENPP2) knock-down by small interfering RNA in breast cancer cells.
Noh JH, Ryu SY, Eun JW, Song J, Ahn YM, Kim SY, Lee SH, Park WS, Yoo NJ, Lee JY, Lee SN, Nam SW
Molecular and cellular biochemistry. 2006 ; 288 (1-2) : 91-106.
PMID 16601922
Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase.
Pradère JP, Tarnus E, Grès S, Valet P, Saulnier-Blache JS
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PMID 17208043
Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma.
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PMID 17192809
The candidate tumor suppressor CST6 alters the gene expression profile of human breast carcinoma cells: down-regulation of the potent mitogenic, motogenic, and angiogenic factor autotaxin.
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PMID 16356477
Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein.
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PMID 1733949
Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid.
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The Journal of biological chemistry. 2006 ; 281 (35) : 25822-25830.
PMID 16829511
Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase.
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The Journal of biological chemistry. 2002 ; 277 (42) : 39436-39442.
PMID 12176993
Cyclic phosphatidic acid is produced by autotaxin in blood.
Tsuda S, Okudaira S, Moriya-Ito K, Shimamoto C, Tanaka M, Aoki J, Arai H, Murakami-Murofushi K, Kobayashi T
The Journal of biological chemistry. 2006 ; 281 (36) : 26081-26088.
PMID 16837466
Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production.
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The Journal of cell biology. 2002 ; 158 (2) : 227-233.
PMID 12119361
Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells.
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PMID 12498389
Autotaxin expression in non-small-cell lung cancer.
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American journal of respiratory cell and molecular biology. 1999 ; 21 (2) : 216-222.
PMID 10423404
Expression of autotaxin mRNA in human hepatocellular carcinoma.
Zhang G, Zhao Z, Xu S, Ni L, Wang X
Chinese medical journal. 1999 ; 112 (4) : 330-332.
PMID 11593532
Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.
van Meeteren LA, Ruurs P, Stortelers C, Bouwman P, van Rooijen MA, Pradère JP, Pettit TR, Wakelam MJ, Saulnier-Blache JS, Mummery CL, Moolenaar WH, Jonkers J
Molecular and cellular biology. 2006 ; 26 (13) : 5015-5022.
PMID 16782887


This paper should be referenced as such :
Clair, T ; Stracke, ML
ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):182-185.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)ENPP2   3357
Entrez_Gene (NCBI)ENPP2    ectonucleotide pyrophosphatase/phosphodiesterase 2
GeneCards (Weizmann)ENPP2
Ensembl hg19 (Hinxton)ENSG00000136960 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000136960 [Gene_View]  ENSG00000136960 [Sequence]  chr8:119557086-119638839 [Contig_View]  ENPP2 [Vega]
ICGC DataPortalENSG00000136960
TCGA cBioPortalENPP2
Genatlas (Paris)ENPP2
SOURCE (Princeton)ENPP2
Genetics Home Reference (NIH)ENPP2
Genomic and cartography
GoldenPath hg38 (UCSC)ENPP2  -     chr8:119557086-119638839 -  8q24.12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ENPP2  -     8q24.12   [Description]    (hg19-Feb_2009)
GoldenPathENPP2 - 8q24.12 [CytoView hg19]  ENPP2 - 8q24.12 [CytoView hg38]
Genome Data Viewer NCBIENPP2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA256687 AI339551 AI375195 AK124910 AK130313
RefSeq transcript (Entrez)NM_001040092 NM_001130863 NM_001330600 NM_006209
Consensus coding sequences : CCDS (NCBI)ENPP2
Gene ExpressionENPP2 [ NCBI-GEO ]   ENPP2 [ EBI - ARRAY_EXPRESS ]   ENPP2 [ SEEK ]   ENPP2 [ MEM ]
Gene Expression Viewer (FireBrowse)ENPP2 [ Firebrowse - Broad ]
GenevisibleExpression of ENPP2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5168
GTEX Portal (Tissue expression)ENPP2
Human Protein AtlasENSG00000136960-ENPP2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)ENPP2
Human Protein Atlas [tissue]ENSG00000136960-ENPP2 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed179 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:17:08 CEST 2021

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