Disease relevance of LNPEP

• Further study to investigate the roles of P-LAP and GLUT4 in ovarian carcinoma is needed [1].
• The tendency toward increased P-LAP expression with advancing grade was observed in serous adenocarcinomas [1].
• In invasive carcinomas, there was a direct correlation between P-LAP immunoreactivity and GLUT4 immunoreactivity (correlation coefficient [r] = 0.58; P < 0.01) [1].
• RESULTS: P-LAP immunoreactivity was detected in 2 of 11 benign cystadenomas [1].
• P-LAP was expressed in 23 of 29 in serous, 15 of 17 endometrioid, 13 of 14 mucinous, and all clear-cell adenocarcinomas [1].

High impact information on LNPEP

• PLAP is not secreted by SRD-12B cells, cholesterol auxotrophs that lack S1P [2].
• In sterol-deprived cells, cleavage by both proteases leads to PLAP secretion [2].
• Grb2 binds with its COOH-terminal SH3 domain to a PLAP motif within TNFR-I and with its NH2-terminal SH3 domain to SOS (son of sevenless) [3].
• Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4(+) T cells and induction of apoptosis [4].
• A monoclonal antibody (H17E2) against placental alkaline phosphatase (PLAP) and testicular placental-like alkaline phosphatase was labelled with indium-111 and used in radioimmunoscintigraphy of 15 patients known or suspected to have germ-cell carcinoma of the testis or carcinoma of the ovary or cervix [5].

Chemical compound and disease context of LNPEP

• P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling [6].
• For this purpose we cross-linked glycosyl-phosphatidylinositol (GPI)-anchored proteins placental alkaline phosphatase (PLAP), Thy-1, influenza virus hemagglutinin (HA), and the raft lipid ganglioside GM1 using antibodies and/or cholera toxin [7].
• RESULTS: We demonstrated the presence of P-LAP, which is identical to cystine aminopeptidase as oxytocinase, in human endometrial adenocarcinoma tissues and found that the expression of P-LAP increase with advances in the grade [8].
• We transfected P-LAP cDNA into A-MEC cells (endometrial adenocarcinoma cell line), and A-MEC-LAP cells displayed a 1.8-fold, 2.0-fold and 1.7-fold increase in IC(50) against paclitaxel, carboplatin and cisplatin respectively [9].
• METHODS: Histologic sections of formalin-fixed, paraffin-embedded specimens from 99 primary endometrial carcinomas were stained for P-LAP using polyclonal P-LAP antibody [10].

Biological context of LNPEP

• Immunoblot analysis demonstrated that the majority of P-LAP/OTase was produced around the time of ovulation [11].
• Further understanding of the function of P-LAP/OTase in the endometrium appears likely to yield insights into the cyclic changes during the normal menstrual cycle [11].
• Thereafter, the membrane-bound P-LAP/OTase was released by apocrine secretion during the period of blastocyst implantation and became depleted toward the time of menstruation [11].
• In the follicular phase, immunoreactive P-LAP/OTase was homogeneously distributed on the plasma membrane and in cytoplasmic granules [11].
• Structure of the human oxytocinase/insulin-regulated aminopeptidase gene and localization to chromosome 5q21 [12].

Anatomical context of LNPEP

• Existence of placental leucine aminopeptidase/oxytocinase/insulin-regulated membrane aminopeptidase in human endometrial epithelial cells [11].
• P-LAP/OTase and its mRNA were localized in endometrial epithelial cells but not in stromal cells [11].
• Human OTASE was assigned to chromosome 5 by hybridization to genomic DNA from characterized somatic cell hybrids [12].
• While P-LAP is translocated from intracellular vesicles to plasma membrane in a stimulus-dependent manner, both A-LAP and L-RAP are retained in the endoplasmic reticulum [13].
• Insulin stimulates translocation of glucose transporter isoform type 4 (GLUT4) and the insulin-responsive aminopeptidase (IRAP) from an intracellular storage pool to the plasma membrane in muscle and fat cells [14].

Associations of LNPEP with chemical compounds

• However, overexpression of FHOS24, lacking the IRAP-binding domain, did not affect insulin-stimulated glucose uptake [14].
• Here, we report that a cell-permeable phosphoinositide-binding peptide induced GLUT4 translocation to the plasma membrane without inhibiting IRAP (insulin-responsive aminopeptidase) endocytosis [15].
• HEK 293T cells transfected with IRAP exhibit typical AT(4) receptor binding characteristics; the AT(4) receptor ligands, angiotensin IV and LVV-hemorphin 7, compete for the binding of [(125)I]Nle(1)-angiotensin IV with IC(50) values of 32 and 140 nm, respectively [16].
• In addition, we demonstrate that the IRAP-binding domain of AS160 falls within its second phosphotyrosine-binding domain and the interaction is not regulated by AS160 phosphorylation [17].
• Of a range of peptides tested, only vasopressin, oxytocin, and met-enkephalin were rapidly cleaved by IRAP [18].

Physical interactions of LNPEP

• The 5'-flanking region of human P-LAP gene contained DNA-binding motifs for several ubiquitous transcription factors such as SP1 and AP2 [19].

Regulatory relationships of LNPEP

• Furthermore, P-LAP overexpression in SKOV3 cells induced the GLUT4 expression [1].
• Conclusions: These findings suggested that P-LAP on the plasma membrane in HUVECs regulates the effects of OT with resolution around OTR [20].
• Ap-2 and Ikaros regulate transcription of human placental leucine aminopeptidase/oxytocinase gene [21].

Other interactions of LNPEP

• Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases [22].
• However, the intracellular localization change that accompanied apocrine secretion, which was observed in P-LAP, was not shown in A-LAP [23].
• The sequence encodes a 960-amino acid protein with significant homology to placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase [22].
• Finally, the OTASE and the human aminopeptidase A gene were subchromosomally localized to 5q21 and 4q25, respectively, by in situ hybridization [12].
• This finding suggests a function for IRAP/P-LAP in the regulation of GLUT4 levels [24].

Analytical, diagnostic and therapeutic context of LNPEP

• Expressions of P-LAP and GLUT-4 in ovarian cancer cells were detected by Western blotting [1].
• Northern blot analysis revealed the increase of P-LAP mRNA levels in placenta in the third trimester compared to the first trimester [25].
• The distribution of IRAP and its mRNA in the brain, determined by immunohistochemistry and hybridization histochemistry, parallels that of the AT(4) receptor determined by radioligand binding [16].
• The availability of a specific antibody against native P-LAP permits the rapid purification and the preliminary immunoassay of the enzyme [26].
• Semi-quantitative RT-PCR and Southern blot analysis showed that IL-1beta also increased P-LAP mRNA, which was abrogated by prior exposure to cycloheximide [27].

References