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. 2004 Feb 1;377(Pt 3):607–616. doi: 10.1042/BJ20031223

Interaction of a farnesylated protein with renal type IIa Na/Pi co-transporter in response to parathyroid hormone and dietary phosphate.

Mikiko Ito 1, Sachi Iidawa 1, Michiyo Izuka 1, Sakiko Haito 1, Hiroko Segawa 1, Masashi Kuwahata 1, Ichiro Ohkido 1, Hiroshi Ohno 1, Ken-Ichi Miyamoto 1
PMCID: PMC1223893  PMID: 14558883

Abstract

Treatment with PTH (parathyroid hormone) or a high-P(i) diet causes internalization of the type IIa sodium-dependent phosphate (Na/P(i) IIa) co-transporter from the apical membrane and its degradation in the lysosome. A dibasic amino acid motif (KR) in the third intracellular loop of the co-transporter is essential for protein's PTH-induced retrieval. To elucidate the mechanism of internalization of Na/P(i) IIa, we identified the interacting protein for the endocytic motif by yeast two-hybrid screening. We found a strong interaction of the Na/P(i) IIa co-transporter with a small protein known as the PEX19 (human peroxisomal farnesylated protein; PxF, Pex19p). PEX19 can bind to the KR motif, but not to a mutant with this motif replaced with NI residues. PEX19 is highly expressed in mouse and rat kidney. Western blot analysis indicates that PEX19 is located in the cytosolic and brush-border membrane fractions (microvilli and the subapical component). Overexpression of PEX19 stimulated the endocytosis of the Na/P(i) IIa co-transporter in opossum kidney cells in the absence of PTH. In conclusion, the present study indicates that PEX19 may be actively involved in controlling the internalization and trafficking of the Na/P(i) IIa co-transporter.

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Selected References

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  1. Braun A., Kammerer S., Weissenhorn W., Weiss E. H., Cleve H. Sequence of a putative human housekeeping gene (HK33) localized on chromosome 1. Gene. 1994 Sep 2;146(2):291–295. doi: 10.1016/0378-1119(94)90308-5. [DOI] [PubMed] [Google Scholar]
  2. Brosius Ute, Dehmel Thomas, Gärtner Jutta. Two different targeting signals direct human peroxisomal membrane protein 22 to peroxisomes. J Biol Chem. 2001 Oct 5;277(1):774–784. doi: 10.1074/jbc.M108155200. [DOI] [PubMed] [Google Scholar]
  3. Custer M., Spindler B., Verrey F., Murer H., Biber J. Identification of a new gene product (diphor-1) regulated by dietary phosphate. Am J Physiol. 1997 Nov;273(5 Pt 2):F801–F806. doi: 10.1152/ajprenal.1997.273.5.F801. [DOI] [PubMed] [Google Scholar]
  4. Fujiki Y. Peroxisome biogenesis and peroxisome biogenesis disorders. FEBS Lett. 2000 Jun 30;476(1-2):42–46. doi: 10.1016/s0014-5793(00)01667-7. [DOI] [PubMed] [Google Scholar]
  5. Gisler S. M., Stagljar I., Traebert M., Bacic D., Biber J., Murer H. Interaction of the type IIa Na/Pi cotransporter with PDZ proteins. J Biol Chem. 2000 Nov 30;276(12):9206–9213. doi: 10.1074/jbc.M008745200. [DOI] [PubMed] [Google Scholar]
  6. Gloeckner C. J., Mayerhofer P. U., Landgraf P., Muntau A. C., Holzinger A., Gerber J. K., Kammerer S., Adamski J., Roscher A. A. Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p. Biochem Biophys Res Commun. 2000 Apr 29;271(1):144–150. doi: 10.1006/bbrc.2000.2572. [DOI] [PubMed] [Google Scholar]
  7. Green J., Debby H., Lederer E., Levi M., Zajicek H. K., Bick T. Evidence for a PTH-independent humoral mechanism in post-transplant hypophosphatemia and phosphaturia. Kidney Int. 2001 Sep;60(3):1182–1196. doi: 10.1046/j.1523-1755.2001.0600031182.x. [DOI] [PubMed] [Google Scholar]
  8. Götte K., Girzalsky W., Linkert M., Baumgart E., Kammerer S., Kunau W. H., Erdmann R. Pex19p, a farnesylated protein essential for peroxisome biogenesis. Mol Cell Biol. 1998 Jan;18(1):616–628. doi: 10.1128/mcb.18.1.616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hernando N., Forgo J., Biber J., Murer H. PTH-Induced downregulation of the type IIa Na/P(i)-cotransporter is independent of known endocytic motifs. J Am Soc Nephrol. 2000 Nov;11(11):1961–1968. doi: 10.1681/ASN.V11111961. [DOI] [PubMed] [Google Scholar]
  10. Hernando Nati, Déliot Nadine, Gisler Serge M., Lederer Eleanor, Weinman Edward J., Biber Jürg, Murer Heini. PDZ-domain interactions and apical expression of type IIa Na/P(i) cotransporters. Proc Natl Acad Sci U S A. 2002 Aug 21;99(18):11957–11962. doi: 10.1073/pnas.182412699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hilfiker H., Hattenhauer O., Traebert M., Forster I., Murer H., Biber J. Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14564–14569. doi: 10.1073/pnas.95.24.14564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jankowski M., Biber J., Murer H. PTH-induced internalization of a type IIa Na/Pi cotransporter in OK-cells. Pflugers Arch. 1999 Oct;438(5):689–693. doi: 10.1007/s004249900093. [DOI] [PubMed] [Google Scholar]
  13. Jankowski M., Hilfiker H., Biber J., Murer H. The opossum kidney cell type IIa Na/P(i) cotransporter is a phosphoprotein. Kidney Blood Press Res. 2001;24(1):1–4. doi: 10.1159/000054198. [DOI] [PubMed] [Google Scholar]
  14. Kammerer S., Arnold N., Gutensohn W., Mewes H. W., Kunau W. H., Höfler G., Roscher A. A., Braun A. Genomic organization and molecular characterization of a gene encoding HsPXF, a human peroxisomal farnesylated protein. Genomics. 1997 Oct 1;45(1):200–210. doi: 10.1006/geno.1997.4914. [DOI] [PubMed] [Google Scholar]
  15. Karim-Jimenez Z., Hernando N., Biber J., Murer H. A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12896–12901. doi: 10.1073/pnas.220394197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Katai K., Segawa H., Haga H., Morita K., Arai H., Tatsumi S., Taketani Y., Miyamoto K., Hisano S., Fukui Y. Acute regulation by dietary phosphate of the sodium-dependent phosphate transporter (NaP(i)-2) in rat kidney. J Biochem. 1997 Jan;121(1):50–55. doi: 10.1093/oxfordjournals.jbchem.a021569. [DOI] [PubMed] [Google Scholar]
  17. Kirchhausen Tom. Clathrin adaptors really adapt. Cell. 2002 May 17;109(4):413–416. doi: 10.1016/s0092-8674(02)00751-1. [DOI] [PubMed] [Google Scholar]
  18. Kocher O., Comella N., Tognazzi K., Brown L. F. Identification and partial characterization of PDZK1: a novel protein containing PDZ interaction domains. Lab Invest. 1998 Jan;78(1):117–125. [PubMed] [Google Scholar]
  19. Lederer E. D., Sohi S. S., Mathiesen J. M., Klein J. B. Regulation of expression of type II sodium-phosphate cotransporters by protein kinases A and C. Am J Physiol. 1998 Aug;275(2 Pt 2):F270–F277. doi: 10.1152/ajprenal.1998.275.2.F270. [DOI] [PubMed] [Google Scholar]
  20. Levi M., Lötscher M., Sorribas V., Custer M., Arar M., Kaissling B., Murer H., Biber J. Cellular mechanisms of acute and chronic adaptation of rat renal P(i) transporter to alterations in dietary P(i). Am J Physiol. 1994 Nov;267(5 Pt 2):F900–F908. doi: 10.1152/ajprenal.1994.267.5.F900. [DOI] [PubMed] [Google Scholar]
  21. Lötscher M., Kaissling B., Biber J., Murer H., Levi M. Role of microtubules in the rapid regulation of renal phosphate transport in response to acute alterations in dietary phosphate content. J Clin Invest. 1997 Mar 15;99(6):1302–1312. doi: 10.1172/JCI119289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lötscher M., Scarpetta Y., Levi M., Halaihel N., Wang H., Zajicek H. K., Biber J., Murer H., Kaissling B. Rapid downregulation of rat renal Na/P(i) cotransporter in response to parathyroid hormone involves microtubule rearrangement. J Clin Invest. 1999 Aug;104(4):483–494. doi: 10.1172/JCI3208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Matsuzono Y., Kinoshita N., Tamura S., Shimozawa N., Hamasaki M., Ghaedi K., Wanders R. J., Suzuki Y., Kondo N., Fujiki Y. Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2116–2121. doi: 10.1073/pnas.96.5.2116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Minami H., Kim J. R., Tada K., Takahashi F., Miyamoto K., Nakabou Y., Sakai K., Hagihira H. Inhibition of glucose absorption by phlorizin affects intestinal functions in rats. Gastroenterology. 1993 Sep;105(3):692–697. doi: 10.1016/0016-5085(93)90884-f. [DOI] [PubMed] [Google Scholar]
  25. Murer H., Hernando N., Forster I., Biber J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev. 2000 Oct;80(4):1373–1409. doi: 10.1152/physrev.2000.80.4.1373. [DOI] [PubMed] [Google Scholar]
  26. Murer H., Lötscher M., Kaissling B., Levi M., Kempson S. A., Biber J. Renal brush border membrane Na/Pi-cotransport: molecular aspects in PTH-dependent and dietary regulation. Kidney Int. 1996 Jun;49(6):1769–1773. doi: 10.1038/ki.1996.264. [DOI] [PubMed] [Google Scholar]
  27. Pfister M. F., Hilfiker H., Forgo J., Lederer E., Biber J., Murer H. Cellular mechanisms involved in the acute adaptation of OK cell Na/Pi-cotransport to high- or low-Pi medium. Pflugers Arch. 1998 Apr;435(5):713–719. doi: 10.1007/s004240050573. [DOI] [PubMed] [Google Scholar]
  28. Pfister M. F., Lederer E., Forgo J., Ziegler U., Lötscher M., Quabius E. S., Biber J., Murer H. Parathyroid hormone-dependent degradation of type II Na+/Pi cotransporters. J Biol Chem. 1997 Aug 8;272(32):20125–20130. doi: 10.1074/jbc.272.32.20125. [DOI] [PubMed] [Google Scholar]
  29. Pfister M. F., Ruf I., Stange G., Ziegler U., Lederer E., Biber J., Murer H. Parathyroid hormone leads to the lysosomal degradation of the renal type II Na/Pi cotransporter. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1909–1914. doi: 10.1073/pnas.95.4.1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Reshkin S. J., Wuarin F., Biber J., Murer H. Parathyroid hormone-induced alterations of protein content and phosphorylation in enriched apical membranes of opossum kidney cells. J Biol Chem. 1990 Sep 5;265(25):15261–15266. [PubMed] [Google Scholar]
  31. Segawa Hiroko, Kaneko Ichiro, Takahashi Akira, Kuwahata Masashi, Ito Mikiko, Ohkido Ichiro, Tatsumi Sawako, Miyamoto Ken-Ichi. Growth-related renal type II Na/Pi cotransporter. J Biol Chem. 2002 Mar 5;277(22):19665–19672. doi: 10.1074/jbc.M200943200. [DOI] [PubMed] [Google Scholar]
  32. Shenolikar S., Voltz J. W., Minkoff C. M., Wade J. B., Weinman E. J. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A. 2002 Aug 8;99(17):11470–11475. doi: 10.1073/pnas.162232699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Takei K., Haucke V. Clathrin-mediated endocytosis: membrane factors pull the trigger. Trends Cell Biol. 2001 Sep;11(9):385–391. doi: 10.1016/s0962-8924(01)02082-7. [DOI] [PubMed] [Google Scholar]
  34. Traebert M., Roth J., Biber J., Murer H., Kaissling B. Internalization of proximal tubular type II Na-P(i) cotransporter by PTH: immunogold electron microscopy. Am J Physiol Renal Physiol. 2000 Jan;278(1):F148–F154. doi: 10.1152/ajprenal.2000.278.1.F148. [DOI] [PubMed] [Google Scholar]
  35. Traebert M., Völkl H., Biber J., Murer H., Kaissling B. Luminal and contraluminal action of 1-34 and 3-34 PTH peptides on renal type IIa Na-P(i) cotransporter. Am J Physiol Renal Physiol. 2000 May;278(5):F792–F798. doi: 10.1152/ajprenal.2000.278.5.F792. [DOI] [PubMed] [Google Scholar]
  36. Wang S., Yue H., Derin R. B., Guggino W. B., Li M. Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity. Cell. 2000 Sep 29;103(1):169–179. doi: 10.1016/s0092-8674(00)00096-9. [DOI] [PubMed] [Google Scholar]
  37. Weinman E. J., Evangelista C. M., Steplock D., Liu M. Z., Shenolikar S., Bernardo A. Essential role for NHERF in cAMP-mediated inhibition of the Na+-HCO3- co-transporter in BSC-1 cells. J Biol Chem. 2001 Sep 4;276(45):42339–42346. doi: 10.1074/jbc.M106153200. [DOI] [PubMed] [Google Scholar]
  38. Werner A., Kempson S. A., Biber J., Murer H. Increase of Na/Pi-cotransport encoding mRNA in response to low Pi diet in rat kidney cortex. J Biol Chem. 1994 Mar 4;269(9):6637–6639. [PubMed] [Google Scholar]

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