Disease relevance of PPAP2A

• Identification of the phosphatidic acid phosphatase type 2a isozyme as an androgen-regulated gene in the human prostatic adenocarcinoma cell line LNCaP [1].
• We demonstrate herein that LPP-1 mRNA is decreased in the majority of ovarian cancers [2].
• PAP2 metastases had a significantly higher proportion of proliferating cells as compared with apoptosing cells, whereas NIH 3T3 metastases had low proliferation and high apoptosis levels [3].
• Liver metastases produced by mesenteric vein injection of B16F1 (murine melanoma), PAP2 (murine H-ras-transformed fibroblast), HT-29 (human colon carcinoma), and MDA-MB-435/HAL (human breast carcinoma) cells were identified and tracked longitudinally [4].
• Here we show that increasing the catalytic activity of LPP1 decreased the pertussis toxin-sensitive stimulation of fibroblast migration by LPA and an LPA-receptor agonist that could not be dephosphorylated [5].

High impact information on PPAP2A

• In this study, we demonstrate that lazaro (laza) encodes a lipid phosphate phosphohydrolase (LPP) that functions during phototransduction [6].
• Peptide sequencing of a candidate phosphatase was consistent with phosphatidic acid phosphatase domain containing 2 (PPAPDC2), an uncharacterized protein that contains a lipid phosphate phosphohydrolase consensus motif [7].
• LPP1 also controls PDGF-induced phosphatidate formation [5].
• These results shed new light on the roles of LPP1 in controlling wound healing and the growth and metastasis of tumors [5].
• We show that intact platelets and platelet membranes actively dephosphorylate LPA and identify the major enzyme responsible as lipid phosphate phosphatase 1 (LPP1) [8].

Chemical compound and disease context of PPAP2A

• Ultraviolet light (UV) sensitivity and photoreactivation of algal virus (cyanophage) LPP-1 were studied after multiplication in host alga Plectonema boryanum in presence of 5-bromouracil (5-BU) alone and in conjunction with sulfanilamide [9].

Biological context of PPAP2A

• Northern analyses revealed that the mRNAs for LPP1 and LPP3 increase in fetal rat lung in late gestation to day 1 after birth [10].
• Kinetic analysis of PAP-2a, -2b, and -2c activity against PA, lysophosphatidic acid, C1P, and S1P presented in mixed micelles of Triton X-100 revealed differences in substrate specificity and susceptibility to inhibition by sphingosine, Zn2+, and propranol [11].
• Two PAP2 cDNAs of 923 and 926 base pairs were identified and subsequently cloned from these cells [12].
• Key structural features described previously in PAP-2a and -2b, including the glycosylation site, putative transmembrane domains, and the proposed catalytic site, are conserved in the novel phosphatase [13].
• Two human isoforms of membrane associated phosphatidic acid phosphatase have been described (PAP-2a and -2b), and both enzymes have been shown to have broad substrate specificity and wide tissue distribution [Kai et al., J. Biol. Chem. 272 (1997) 24572-24578] [13].

Anatomical context of PPAP2A

• Pulmonary lipid phosphate phosphohydrolase (LPP) was shown previously to hydrolyze phosphatidic acid and lysophosphatidic acid in purified rat lung plasma membranes [10].
• PAP-2b was expressed almost ubiquitously in all human tissues examined, whereas the expression of PAP-2a was relatively variable, being extremely low in the placenta and thymus [14].
• In HeLa cells, the transcription of PAP-2a was not affected by different stimuli, whereas PAP-2b was induced (up to 3-fold) by epidermal growth factor [14].
• Here, we demonstrate the presence of a Mg(2+)-independent and N-ethymaleimide-insensitive PAP2 activity in cultured guinea-pig airway smooth muscle (ASM) cells [12].
• Transient expression of gpPAP2a2 in Cos-7 cells resulted in an approx. 4-fold increase in Mg(2+)-independent PAP activity, thereby confirming that gpPAP2a2 is another catalytically active member of an extended PAP2 family [12].

Associations of PPAP2A with chemical compounds

• Members of the type 2 phosphatidic acid phosphatase (PAP2) family catalyse the dephosphorylation of phosphatidic acid (PA), lysophosphatidate and sphingosine 1-phosphate [12].
• A 322-base pair cDNA fragment that was consistently induced by the synthetic androgen R1881 revealed 100% homology with the human phosphatidic acid phosphatase type 2a isozyme very recently reported by Kai et al [1].
• Induction of PAP-2a mRNA was not affected by the protein synthesis inhibitor cycloheximide and was accompanied by a marked increase in PAP-2 activity as measured by the conversion of phosphatidic acid into diacylglycerol in membrane fractions of LNCaP [1].
• The steroid specificity of PAP-2a mRNA regulation was found to be in agreement with the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells, supporting the involvement of the androgen receptor in the induction process [1].
• LPP is Mg(2+) independent and sulfhydryl reagent insensitive [15].

Other interactions of PPAP2A

• The pulmonary LPP1 and LPP3 isoforms are essentially identical to the previously cloned rat liver and intestinal LPPs, respectively, and the LPP1a isoform has 80% sequence identity to the human homolog [10].
• Other significant differences between gpPAP2a1/2 and hPAP2a, hPAP2b and hPAP2c occur at the cytoplasmic C-terminal [12].
• Furthermore, low basal levels of PAP-2a mRNA and absence of androgen inducibility were observed in the poorly differentiated and androgen receptor-negative cell lines PC-3 and DU-145 [1].
• Two isoforms, presumed to be alternative splice variants from a single gene, designated as PAP2-alpha1 and PAP2-alpha2, have been cloned and expressed [16].
• The expression of phosphatidic acid phosphatase 2a, which hydrolyzes lipids to generate diacylglycerol, is regulated by p73, a member of the p53 family [17].

Analytical, diagnostic and therapeutic context of PPAP2A

• To better investigate the nature of pulmonary LPP isoforms and their role in the lung, LPPs were cloned by RT-PCR from both adult rat lung and type II cell RNA [10].
• The inducibility of PAP-2a mRNA by androgens was confirmed by Northern blot hybridization [1].

References