Gene Summary for NIH-1841
Functional Category: enzyme-phosphodiesterase
Cell Location: extracellular
Mouse Nucleotide Accession #: NM_015744
Human Nucleotide Accession #: NM_006209

The gene of interest is mouse Enpp2 (ectonucleotide pyrophosphatase/phosphodiesterase 2), ortholog of human ENPP2. Aliases include ATX, Npps2, Autotaxin, NPP2, ATX-X, PDNP2, LysoPLD, FLJ26803, and PD-IALPHA.

ENPP2 is a secreted enzyme that primarily catalyzes the hydrolysis of lysophosphatidylcholine to form lysophosphatidic acid (LPA) (Koike et al, 2006; Xie and Meier, 2004). The enzyme is also capable of catalyzing the hydrolysis of sphingosylphosphoryl choline to form sphingosine 1-phosphate (S1P) (Dennis et al, 2005; van Meeteren et al, 2005). Both LPA and S1P function as lipid mediators that bind with and activate specific G protein-coupled receptors (Ishii et al, 2004). ENPP2 likely plays a role in processes such as neurogenesis, oligodendrocyte differentiation, myelination (van Meeteren et al, 2005), angiogenesis, metastasis (van Meeteren et al, 2006), apoptosis (Song et al, 2005), adipocyte insulin resistance (Boucher et al, 2005), glioblastoma cell migration (Kishi et al, 2006), and keratinocyte cell migration (Mazereeuw-Hautier et al, 2005).

Van Meeteren and colleagues (2006) investigated the physiological role of ENPP2 using knockout mice. They showed that ENPP2 homozygous null mice die at embryonic day 9.5, displaying profound vascular defects in the embryo and yolk sac. They also showed that ENPP2 homozygous null mice display allantois malformation, neural tube defects, and asymmetric head folds at embryonic day 8.5. Van Meeteren and colleagues concluded that ENPP2 is the major LPA-producing enzyme and that ENPP2 plays an important role in blood vessel formation during development.

Phenotypic Summary for NIH-1841
Genetic data indicate that this mutation resulted in lethality of the homozygous mutants. The heterozygous mice exhibited a decreased median serum IL-6 response and slightly decreased median TNF-alpha and MCP-1 responses to LPS challenge when compared with their wild-type littermates and the historical mean.

Disruption of the target gene was confirmed by Southern hybridization analysis.

Genetics project Specific Summary : NIH-1841
Homozygous lethal.

Mouse Gene Sequence Information
Nucleotide Reference: NM_015744 ACCESSION:NM_015744 NID: gi 7657450 ref NM_015744.1 Mus musculus ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2), mRNA
Protein Reference: Q9R1E6 ACCESSION:Q9R1E6 NID: Mus musculus (Mouse). Ectonucleotide pyrophosphatase/phosphodiesterase 2 (E-NPP 2) (Phosphodiesterase I/nucleotide pyrophosphatase 2) (Phosphodiesterase I alpha) (PD-Ialpha) [Includes: Alkaline phosphodiesterase I (EC; Nucleotide pyrophosphatase (EC (NPPase)]. MOUSESPTRNRDB
Entrez Gene: 18606

Human Gene Sequence Information
Nucleotide Reference: NM_006209 ACCESSION:NM_006209 NID: gi 20070229 ref NM_006209.2 Homo sapiens ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin) (ENPP2), mRNA
Protein Reference: Q13822 ACCESSION:Q13822 NID: Homo sapiens (Human). AUTOTAXIN-T. HUMANSPTRNRDB
Entrez Gene: 5168

Bibliographic References
Title Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid.
Author[s] Kishi Yasuhiro, Okudaira Shinichi, Tanaka Masayuki, Hama Kotaro, Shida Dai, Kitayama Joji, Yamori Takao, Aoki Junken, Fujimaki Takamitsu, Arai Hiroyuki
Journal J Biol Chem. 06/23/2006; 281:17492-500

Title The N-terminal hydrophobic sequence of autotaxin (ENPP2) functions as a signal peptide.
Author[s] Koike Seiichi, Keino-Masu Kazuko, Ohto Tatsuyuki, Masu Masayuki
Journal Genes Cells. 02/01/2006; 11:133-42

Title Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.
Author[s] van Meeteren Laurens A, Ruurs Paula, Stortelers Catelijne, Bouwman Peter, van Rooijen Marga A, Pradère Jean Philippe, Pettit Trevor R, Wakelam Michael J O, Saulnier-Blache Jean Sébastien, Mummery Christine L, Moolenaar Wouter H, Jonkers Jos
Journal Mol Cell Biol. 07/01/2006; 26:5015-22

Title Phosphodiesterase-Ialpha/autotaxin (PD-Ialpha/ATX): a multifunctional protein involved in central nervous system development and disease.
Author[s] Dennis Jameel, Nogaroli Luciana, Fuss Babette
Journal J Neurosci Res. 12/15/2005; 82:737-42

Title Autotaxin (lysoPLD/NPP2) protects fibroblasts from apoptosis through its enzymatic product, lysophosphatidic acid, utilizing albumin-bound substrate.
Author[s] Song Jaehwi, Clair Timothy, Noh Ji Heon, Eun Jung Woo, Ryu So Yeon, Lee Shi Nae, Ahn Young Min, Kim Su Young, Lee Sug Hyung, Park Won Sang, Yoo Nam Jin, Lee Jung Young, Nam Suk Woo
Journal Biochem Biophys Res Commun. 11/25/2005; 337:967-75

Title Production of lysophosphatidic acid in blister fluid: involvement of a lysophospholipase D activity.
Author[s] Mazereeuw-Hautier Juliette, Gres Sandra, Fanguin Madie, Cariven Clotilde, Fauvel Josette, Perret Bertrand, Chap Hugues, Salles Jean-Pierre, Saulnier-Blache Jean-Sébastien
Journal J Invest Dermatol. 09/01/2005; 125:421-7

Title Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate.
Author[s] van Meeteren Laurens A, Ruurs Paula, Christodoulou Evangelos, Goding James W, Takakusa Hideo, Kikuchi Kazuya, Perrakis Anastassis, Nagano Tetsuo, Moolenaar Wouter H
Journal J Biol Chem. 06/03/2005; 280:21155-61

Title Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression.
Author[s] Boucher J, Quilliot D, Pradères J P, Simon M F, Grès S, Guigné C, Prévot D, Ferry G, Boutin J A, Carpéné C, Valet P, Saulnier-Blache J S
Journal Diabetologia. 03/01/2005; 48:569-77

Title Lysophospholipase D and its role in LPA production.
Author[s] Xie Yuhuan, Meier Kathryn E
Journal Cell Signal. 09/01/2004; 16:975-81

Title Lysophospholipid receptors: signaling and biology.
Author[s] Ishii Isao, Fukushima Nobuyuki, Ye Xiaoqin, Chun Jerold
Journal Annu Rev Biochem. 01/01/2004; 73:321-54

Mutation Information
Mutation Type: Homologous Recombination (standard)
Description: The gene consists of 25 exons, with the start codon located in exon 1 (NCBI accession NM_015744.1). Exons 1 and 2 were targeted.

Confidential Information

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