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Gene Review

ALPPL2  -  alkaline phosphatase, placental-like 2

Homo sapiens

Synonyms: ALP-1, ALPG, ALPPL, Alkaline phosphatase Nagao isozyme, Alkaline phosphatase, placental-like, ...
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Disease relevance of ALPPL2

  • A431 human epidermoid carcinoma cells monophenotypically express the placental alkaline phosphatase (PLAP)-like enzyme shown by its catalytic and antigenic characteristics, properties which are shared by the Nagao isozyme [1].
  • This peptide elicited rabbit polyclonal antibodies that reacted specifically with the seminoma Nagao isozyme but not with PLAP in electrophoretic transfer blots [2].
  • Administration of sodium butyrate to choriocarcinoma cells greatly increased the transcription rate of the GCAP gene, resulting in an increase in mRNA expression and enzyme biosynthesis [3].
  • Thus, these results indicate that this colon cancer cell alkaline phosphatase is likely to represent an allelic variant encoded at the germ cell alkaline phosphatase locus [4].
  • Antibodies to TNAP and PLAP/GCAP showed positivity in CIS, seminoma, and embryonal carcinoma [5].

High impact information on ALPPL2

  • Single photon responses were compared in wild-type and transgenic retinal rods with and without guanylate cyclase activating protein (GCAP) to disrupt Ca(2+)-dependent feedback regulation of guanylate cyclase (see Burns et al. in this issue of Neuron) [6].
  • They will also enable evaluation of the therapeutic potential of bifunctional antibodies for T-cell recruitment and destruction of GCAP/PLAP-producing tumor cells [7].
  • The expression of GCAP in these FVB/N transgenic mice induces a cellular immune tolerance to GCAP [7].
  • A 450-bp promoter sequence directs the expression of GCAP to the intestine and endothelial cells, while a 5' sequence of 1.7 kb directs GCAP expression to the spermatogenic lineage and to the eight-cell through the blastocyst stage of preimplantation development [7].
  • When mouse fibrosarcoma MO4 cells (C3H derived), stably transfected with the cloned GCAP gene, were injected s.c. in nontransgenic control (C3H x FVB/N) hybrid mice, GCAP-positive tumor cells were rejected [7].

Chemical compound and disease context of ALPPL2


Biological context of ALPPL2

  • Nine GCAP phenotypes were identified, interacting with each antibody at a lower affinity than was seen for the more common PLAP phenotypes [11].
  • Antibody affinity is higher for the free hydrophilic dimeric forms of PLAP and GCAP, and is not influenced by the degree of glycation [11].
  • Our data suggest that the uncompetitive inhibition of GCAP by L-Leu is due to an enzymatically critical conformational change in a loop region proximal to the active site of the enzyme, induced by substitution of a single amino acid residue [12].
  • The conformational change accompanying mutagenesis of Glu429 in PLAP, is important in view of the recent identification of Gly429 as the major determinant of the unique GCAP inhibition by the uncompetitive inhibitor L-Leu [12].
  • The deduced amino acid sequence of the Nagao isozyme indicates that the mature molecule is composed of 513 amino acids, of which 12 residues are different from the sequence of PLAP (98% homology) [2].

Anatomical context of ALPPL2

  • The identification of a cell line such as A431 with enhanced expression in the amount of the PLAP-like enzyme and which can be further enhanced by modulating agents will facilitate studies of the differences and the similarities between this protein and other variants of PLAP [1].
  • The evolution of the alkaline phosphatase (AP) gene family has lead to the existence in humans of one tissue-nonspecific (TNAP) and three tissue-specific isozymes, i.e. intestinal (IAP), germ cell (GCAP), and placental AP (PLAP) [13].
  • In addition to these enzymes, there is a heat-stable activity in the thymus and testis that is similar but not identical to the PLAP (the PLAP-like enzyme) [14].
  • Human choriocarcinoma cells, the malignant trophoblasts, synthesize germ cell alkaline phosphatase (GCAP) which shares 98% sequence identity with the placental alkaline phosphatase (AP) [3].
  • The oncodevelopmental biology of the germ cell and its excessive GCAP eutopic expression in neoplasia are noted, and there is reason to suggest that the enzyme may serve to guide migratory cells and to transport specific molecules such as fat and immunoglobulins across membranes [15].

Associations of ALPPL2 with chemical compounds

  • Protein sequence deduced from complementary DNA analysis suggests that GCAP contains two potential sites for asparagine (N)-linked glycosylation [3].
  • Since the active form of AP is a homodimer, our data indicate that the glycan moieties are not required for the dimerization and catalytic activity of GCAP [3].
  • By substituting Gly-429 of GCAP with a series of amino acids, we demonstrate that the relative sensitivities of these mutants to L-leucine, EDTA, and heat inhibition are, in general, parallel [16].
  • However, the Ser-429 and His-429 mutants were more resistant to EDTA and heat inhibition than the wild-type GCAP, but were equally sensitive to L-leucine inhibition [16].
  • Replacement of codon 429 with Gly in GCAP leads to destabilization and loosening of the metal binding [16].

Other interactions of ALPPL2


Analytical, diagnostic and therapeutic context of ALPPL2


  1. Characterization of the placental alkaline phosphatase-like (Nagao) isozyme on the surface of A431 human epidermoid carcinoma cells. Jemmerson, R., Shah, N., Takeya, M., Fishman, W.H. Cancer Res. (1985) [Pubmed]
  2. Seminoma-derived Nagao isozyme is encoded by a germ-cell alkaline phosphatase gene. Millán, J.L., Manes, T. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  3. Transcriptional regulation and the effects of sodium butyrate and glycosylation on catalytic activity of human germ cell alkaline phosphatase. Pan, C.J., Sartwell, A.D., Chou, J.Y. Cancer Res. (1991) [Pubmed]
  4. Molecular cloning of complementary DNAs encoding alkaline phosphatase in human colon cancer cells. Gum, J.R., Hicks, J.W., Sack, T.L., Kim, Y.S. Cancer Res. (1990) [Pubmed]
  5. Heterogeneity in alkaline phosphatase isozyme expression in human testicular germ cell tumours: An enzyme-/immunohistochemical and molecular analysis. Roelofs, H., Manes, T., Janszen, T., Millán, J.L., Oosterhuis, J.W., Looijenga, L.H. J. Pathol. (1999) [Pubmed]
  6. Open the loop: dissecting feedback regulation of a second messenger transduction cascade. Detwiler, P. Neuron (2002) [Pubmed]
  7. Transgenic mice expressing the tumor marker germ cell alkaline phosphatase: an in vivo tumor model for human cancer antigens. Narisawa, S., Smans, K.A., Avis, J., Hoylaerts, M.F., Millán, J.L. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  8. Induction of germ-cell alkaline phosphatase by butyrate and cyclic AMP in BeWo choriocarcinoma cells. Telfer, J.F., Green, C.D. Biochem. J. (1993) [Pubmed]
  9. Identification and characterization of an androgen-responsive gene encoding an aci-reductone dioxygenase-like protein in the rat prostate. Oram, S., Jiang, F., Cai, X., Haleem, R., Dincer, Z., Wang, Z. Endocrinology (2004) [Pubmed]
  10. Electrophoretic heterogeneity of alkaline phosphatase isozymes in seminoma and normal testis. Koshida, K., Stigbrand, T., Hisazumi, H., Wahren, B. Tumour Biol. (1989) [Pubmed]
  11. Enzyme immunoassay of human placental and germ-cell alkaline phosphatase in serum. Hendrix, P.G., Hoylaerts, M.F., Nouwen, E.J., De Broe, M.E. Clin. Chem. (1990) [Pubmed]
  12. Site-directed mutagenesis and epitope-mapped monoclonal antibodies define a catalytically important conformational difference between human placental and germ cell alkaline phosphatase. Hoylaerts, M.F., Millán, J.L. Eur. J. Biochem. (1991) [Pubmed]
  13. Structural evidence of functional divergence in human alkaline phosphatases. Le Du, M.H., Millan, J.L. J. Biol. Chem. (2002) [Pubmed]
  14. Two gene duplication events in the evolution of the human heat-stable alkaline phosphatases. Knoll, B.J., Rothblum, K.N., Longley, M. Gene (1987) [Pubmed]
  15. Biology of human alkaline phosphatases with special reference to cancer. Millán, J.L., Fishman, W.H. Critical reviews in clinical laboratory sciences. (1995) [Pubmed]
  16. Mutation of a single amino acid converts germ cell alkaline phosphatase to placental alkaline phosphatase. Watanabe, T., Wada, N., Kim, E.E., Wyckoff, H.W., Chou, J.Y. J. Biol. Chem. (1991) [Pubmed]
  17. Structural and functional analysis of human germ cell alkaline phosphatase by site-specific mutagenesis. Watanabe, T., Wada, N., Chou, J.Y. Biochemistry (1992) [Pubmed]
  18. Gonadoblastoma: evidence for a stepwise progression to dysgerminoma in a dysgenetic ovary. Pauls, K., Franke, F.E., Büttner, R., Zhou, H. Virchows Arch. (2005) [Pubmed]
  19. Detection of germ-cell tumor cells in peripheral blood progenitor cell harvests: impact on clinical outcome. Hildebrandt, M., Rick, O., Salama, A., Siegert, W., Huhn, D., Beyer, J. Clin. Cancer Res. (2000) [Pubmed]
  20. Fine needle aspiration cytology of primary mediastinal germ cell tumors. Motoyama, T., Yamamoto, O., Iwamoto, H., Watanabe, H. Acta Cytol. (1995) [Pubmed]
  21. Germ cell alkaline phosphatase in human seminal plasma following vasectomy. Lewis-Jones, D.I., Johnson, P.M., Desmond, A.D., McLaughlin, P.J. British journal of urology. (1992) [Pubmed]
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