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Gene Review

NPY4R  -  neuropeptide Y receptor Y4

Homo sapiens

Synonyms: NPY4-R, Neuropeptide Y receptor type 4, PP1, PPYR1, Pancreatic polypeptide receptor 1, ...
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Disease relevance of PPYR1


Psychiatry related information on PPYR1

  • Accumulating evidence indicates that serine/threonine (Ser/Thr) protein phosphatases (PPs), such as PP1, PP2A and PP2B, participate in the neurodegenerative progress in Alzheimer's disease (AD) [5].

High impact information on PPYR1

  • The protein serine/threonine phosphatase protein phosphatase-1 (PP1) is a ubiquitous eukaryotic enzyme that regulates a variety of cellular processes through the dephosphorylation of dozens of substrates [6].
  • In addition, PP1 plays a key role in the recovery from stress but promotes apoptosis when cells are damaged beyond repair [6].
  • Finally, PP1 promotes the exit from mitosis and maintains cells in the G1 or G2 phases of the cell cycle [6].
  • In this review we discuss how PP1 affects the biochemistry and physiology of eukaryotic cells [6].
  • Because the only known targets of okadaic acid are the catalytic subunits PP1 and PP2A, these enzymes are crucial components of two basic functions carried out by cells: growth and division [7].

Chemical compound and disease context of PPYR1

  • Furthermore, the V804M/E805K tandem lesion confers resistance to the small molecule receptor tyrosine kinase inhibitor, PP1, suggesting a mode of action distinct from that known for classical MEN 2B mutations [8].
  • These data suggest that PA functions as a specific regulator of PP1 and may reverse or counteract those effects of ceramide that are mediated by PP1, such as apoptosis and retinoblastoma gene product dephosphorylation [9].
  • ERK activation by the agonist U46619 was rapid, sensitive to pertussis toxin, and significantly abrogated by the tyrosine kinase inhibitors genistein and PP1 [10].
  • To evaluate the involvement of protein phosphatases (PP) in differentiation of human myelogenous leukemia HL-60 cells, we made use of potent inhibitors of PP1 and PP2A, calyculin-A (CAL-A) and okadaic acid (OKA) [11].
  • This effect was partially inhibited by Ro 318220, GF 109203X, U73122, and SB203580, and blocked or nearly completely inhibited by PP1, pertussis toxin, LY294002, PD98059, and AACOCF3 [12].

Biological context of PPYR1


Anatomical context of PPYR1


Associations of PPYR1 with chemical compounds

  • Also, the rat Y4 tolerates alanine in position 34 since p[Ala(34)]NPY bound with similar affinity as pNPY while the affinity for hY4 and gpY4 decreased about 50-fold [21].
  • The most striking result was the increase in affinity for the rat receptor, but not for human or guinea pig, when amino acid 34 was replaced with proline; [Ahx(8-20),Pro(34)]NPY bound to the rat Y4 receptor with 20-fold higher affinity than [Ahx(8-20)]NPY [21].
  • These peptides exert most of their biological effects through five G-protein coupled receptors termed Y1, Y2, Y4, Y5 and y6 that mediate either inhibition adenylate cyclase or increases in intracellular calcium [22].
  • Microcystin-LR, a PP1 inhibitor, also attenuated I-2 binding to neurabins [23].
  • Phenylarsine oxide, an inhibitor of phosphatase specific for focal adhesion kinase, and PP1, an inhibitor of src kinase family, significantly suppressed motility of the cells [24].

Physical interactions of PPYR1

  • Thus, the carboxyl-terminal region of PP seems to be the most important part of the peptide for high affinity binding to hPP1 [25].
  • Intermolecular interactions within the AKAP220 signaling complex further contribute to PP1 inhibition as addition of the PKA regulatory subunit (RII) enhances phosphatase inhibition [26].
  • By contrast, abolishing PP1 binding to neurabin II maintains phosphorylation levels of Dcx, leading to a retention of Dcx at F-actin [27].
  • Therefore, PP1 may interact with EGF receptor-like molecules to trigger its different biological activities [28].

Regulatory relationships of PPYR1

  • PP1 treatment blocks EGF-induced activation of the anti-apoptotic protein kinase Akt suggesting that Src may regulate activation of Akt, perhaps by a Src --> c-Cbl --> phosphatidylinositol 3'-kinase --> Akt pathway [29].
  • Conversely, treatment of cells with the Src-inhibitors PP1 or herbimycin A resulted in complete suppression of collagen type I-induced E-cadherin decrease [30].
  • Analysis of truncated PP1c and chimeric PP1/2A catalytic subunits suggests that AKAP220 inhibits the phosphatase in a manner distinct from all known PP1 inhibitors and toxins [26].
  • In support of this, inhibition of Src kinase activity by PP1 or siRNA blocked PAR-2-induced EGFR signaling cascade and cell growth [31].

Other interactions of PPYR1

  • Pancreatic polypeptide (PP) potently displaced (125)I-1229U91 from the Y4 receptor, but displayed little affinity for Y1 [19].
  • BIBO 3304 showed low affinity for the human Y2 receptor, human and rat Y4 receptor as well as for the human and rat Y5 receptor (IC50 values > 1000 nM) [32].
  • Because these data may identify the receptor as primarily a PP receptor, we have named it PP1 [33].
  • These effects are mediated by up to 6 G protein coupled receptors designated Y1, Y2, Y3, Y4, Y5 and y6 [34].
  • PYY acts through Y-receptor subtypes: Y1, Y2, Y4 and Y5 in humans [35].

Analytical, diagnostic and therapeutic context of PPYR1

  • Clones for the PP1 receptor were obtained by PCR using sequence information for the neuropeptide Y receptor Y1 from several species [15].
  • By in situ hybridization, expression of Y1 receptor mRNA was restricted to the smooth muscle layer of pial vessels, whereas no specific signals were detected for either Y2, Y4, or Y5 receptors [36].
  • Immunofluorescence indicated that the Y4 receptor was not internalized within the cells after 24-h treatment with 10 nM hPP [37].
  • Moreover, based on the results obtained with histological techniques such as in situ hybridization, immunohistochemistry and ligand binding, we summarize data on the hypothalamic distribution of the known NPY receptors, the Y1 Y2, Y4 and Y5 receptors as best characterized to date [38].
  • We used high-resolution video microscopy to visualize microtubule dynamic instability in extracts of interphase sea urchin eggs and to analyze the changes that occur upon addition of 0.8-2.5 microM okadaic acid, an inhibitor of phosphatase 1 and 2A (PP1, PP2a) (Bialojan, D., and A. Takai. 1988. Biochem. J. 256:283-290) [39].


  1. The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity. Wu, D.Y., Tkachuck, D.C., Roberson, R.S., Schubach, W.H. J. Biol. Chem. (2002) [Pubmed]
  2. Internalization of cloned pancreatic polypeptide receptors is accelerated by all types of Y4 agonists. Parker, M.S., Sah, R., Sheriff, S., Balasubramaniam, A., Parker, S.L. Regul. Pept. (2005) [Pubmed]
  3. Genetic alterations and expression of the protein phosphatase 1 genes in human cancers. Takakura, S., Kohno, T., Manda, R., Okamoto, A., Tanaka, T., Yokota, J. Int. J. Oncol. (2001) [Pubmed]
  4. Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and production of vascular endothelial growth factor. Yu, A., Somasundar, P., Balsubramaniam, A., Rose, A.T., Vona-Davis, L., McFadden, D.W. J. Surg. Res. (2002) [Pubmed]
  5. Role of serine/threonine protein phosphatase in Alzheimer's disease. Tian, Q., Wang, J. Neurosignals (2002) [Pubmed]
  6. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Ceulemans, H., Bollen, M. Physiol. Rev. (2004) [Pubmed]
  7. Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth. Mumby, M.C., Walter, G. Physiol. Rev. (1993) [Pubmed]
  8. RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B. Cranston, A.N., Carniti, C., Oakhill, K., Radzio-Andzelm, E., Stone, E.A., McCallion, A.S., Hodgson, S., Clarke, S., Mondellini, P., Leyland, J., Pierotti, M.A., Whittaker, J., Taylor, S.S., Bongarzone, I., Ponder, B.A. Cancer Res. (2006) [Pubmed]
  9. Phosphatidic acid is a potent and selective inhibitor of protein phosphatase 1 and an inhibitor of ceramide-mediated responses. Kishikawa, K., Chalfant, C.E., Perry, D.K., Bielawska, A., Hannun, Y.A. J. Biol. Chem. (1999) [Pubmed]
  10. Thromboxane prostanoid receptor signals through Gi protein to rapidly activate extracellular signal-regulated kinase in human airways. Citro, S., Ravasi, S., Rovati, G.E., Capra, V. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  11. Augmentation of retinoic acid-induced granulocytic differentiation in HL-60 leukemia cells by serine/threonine protein phosphatase inhibitors. Morita, K., Nishikawa, M., Kobayashi, K., Deguchi, K., Ito, M., Nakano, T., Shima, H., Nagao, M., Kuno, T., Tanaka, C. FEBS Lett. (1992) [Pubmed]
  12. Endothelial NADPH oxidase: mechanism of activation by low-density lipoprotein. O'Donnell, R.W., Johnson, D.K., Ziegler, L.M., DiMattina, A.J., Stone, R.I., Holland, J.A. Endothelium (2003) [Pubmed]
  13. Neuropeptide Y receptor genes mapped in human and mouse: receptors with high affinity for pancreatic polypeptide are not clustered with receptors specific for neuropeptide Y and peptide YY. Lutz, C.M., Richards, J.E., Scott, K.L., Sinha, S., Yang-Feng, T.L., Frankel, W.N., Thompson, D.A. Genomics (1997) [Pubmed]
  14. Assignment of the Y4 receptor gene (PPYR1) to human chromosome 10q11.2 and mouse chromosome 14. Darby, K., Eyre, H.J., Lapsys, N., Copeland, N.G., Gilbert, D.J., Couzens, M., Antonova, O., Sutherland, G.R., Jenkins, N.A., Herzog, H. Genomics (1997) [Pubmed]
  15. The cloned rat pancreatic polypeptide receptor exhibits profound differences to the orthologous receptor. Lundell, I., Statnick, M.A., Johnson, D., Schober, D.A., Starbäck, P., Gehlert, D.R., Larhammar, D. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  16. Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone release. Small, C.J., Morgan, D.G., Meeran, K., Heath, M.M., Gunn, I., Edwards, C.M., Gardiner, J., Taylor, G.M., Hurley, J.D., Rossi, M., Goldstone, A.P., O'Shea, D., Smith, D.M., Ghatei, M.A., Bloom, S.R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  17. Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. Bard, J.A., Walker, M.W., Branchek, T.A., Weinshank, R.L. J. Biol. Chem. (1995) [Pubmed]
  18. NPY regulates catecholamine secretion from human adrenal chromaffin cells. Cavadas, C., Silva, A.P., Mosimann, F., Cotrim, M.D., Ribeiro, C.A., Brunner, H.R., Grouzmann, E. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  19. Pharmacological characterization of (125)I-1229U91 binding to Y1 and Y4 neuropeptide Y/Peptide YY receptors. Schober, D.A., Gackenheimer, S.L., Heiman, M.L., Gehlert, D.R. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  20. Neuropeptide Y, Y1, Y2 and Y4 receptors mediate Y agonist responses in isolated human colon mucosa. Cox, H.M., Tough, I.R. Br. J. Pharmacol. (2002) [Pubmed]
  21. Studies of the human, rat, and guinea pig Y4 receptors using neuropeptide Y analogues and two distinct radioligands. Berglund, M.M., Lundell, I., Eriksson, H., Söll, R., Beck-Sickinger, A.G., Larhammar, D. Peptides (2001) [Pubmed]
  22. Introduction to the reviews on neuropeptide Y. Gehlert, D.R. Neuropeptides (2004) [Pubmed]
  23. Neurabins recruit protein phosphatase-1 and inhibitor-2 to the actin cytoskeleton. Terry-Lorenzo, R.T., Elliot, E., Weiser, D.C., Prickett, T.D., Brautigan, D.L., Shenolikar, S. J. Biol. Chem. (2002) [Pubmed]
  24. Functional involvement of src and focal adhesion kinase in a CD99 splice variant-induced motility of human breast cancer cells. Lee, H.J., Kim, E., Jee, B., Hahn, J.H., Han, K., Jung, K.C., Park, S.H., Lee, H. Exp. Mol. Med. (2002) [Pubmed]
  25. Characterization of the peptide binding requirements for the cloned human pancreatic polypeptide-preferring receptor. Gehlert, D.R., Schober, D.A., Beavers, L., Gadski, R., Hoffman, J.A., Smiley, D.L., Chance, R.E., Lundell, I., Larhammar, D. Mol. Pharmacol. (1996) [Pubmed]
  26. Multiple interactions within the AKAP220 signaling complex contribute to protein phosphatase 1 regulation. Schillace, R.V., Voltz, J.W., Sim, A.T., Shenolikar, S., Scott, J.D. J. Biol. Chem. (2001) [Pubmed]
  27. Neurabin II mediates doublecortin-dephosphorylation on actin filaments. Tsukada, M., Prokscha, A., Eichele, G. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  28. Structure of a paralytic peptide from an insect, Manduca sexta. Yu, X.Q., Prakash, O., Kanost, M.R. J. Pept. Res. (1999) [Pubmed]
  29. Inhibition of Src family kinases blocks epidermal growth factor (EGF)-induced activation of Akt, phosphorylation of c-Cbl, and ubiquitination of the EGF receptor. Kassenbrock, C.K., Hunter, S., Garl, P., Johnson, G.L., Anderson, S.M. J. Biol. Chem. (2002) [Pubmed]
  30. Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Menke, A., Philippi, C., Vogelmann, R., Seidel, B., Lutz, M.P., Adler, G., Wedlich, D. Cancer Res. (2001) [Pubmed]
  31. Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation. Caruso, R., Pallone, F., Fina, D., Gioia, V., Peluso, I., Caprioli, F., Stolfi, C., Perfetti, A., Spagnoli, L.G., Palmieri, G., Macdonald, T.T., Monteleone, G. Am. J. Pathol. (2006) [Pubmed]
  32. Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents. Wieland, H.A., Engel, W., Eberlein, W., Rudolf, K., Doods, H.N. Br. J. Pharmacol. (1998) [Pubmed]
  33. Cloning of a human receptor of the NPY receptor family with high affinity for pancreatic polypeptide and peptide YY. Lundell, I., Blomqvist, A.G., Berglund, M.M., Schober, D.A., Johnson, D., Statnick, M.A., Gadski, R.A., Gehlert, D.R., Larhammar, D. J. Biol. Chem. (1995) [Pubmed]
  34. Cloning and characterization of Rhesus monkey neuropeptide Y receptor subtypes. Gehlert, D.R., Yang, P., George, C., Wang, Y., Schober, D., Gackenheimer, S., Johnson, D., Beavers, L.S., Gadski, R.A., Baez, M. Peptides (2001) [Pubmed]
  35. Peptide YY(1-36) and Peptide YY(3-36): Part I. Distribution, release and actions. Ballantyne, G.H. Obesity surgery : the official journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. (2006) [Pubmed]
  36. Expression of neuropeptide Y receptors mRNA and protein in human brain vessels and cerebromicrovascular cells in culture. Abounader, R., Elhusseiny, A., Cohen, Z., Olivier, A., Stanimirovic, D., Quirion, R., Hamel, E. J. Cereb. Blood Flow Metab. (1999) [Pubmed]
  37. Functional and molecular properties of the human recombinant Y4 receptor: resistance to agonist-promoted desensitization. Voisin, T., Goumain, M., Lorinet, A.M., Maoret, J.J., Laburthe, M. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  38. Distribution of NPY receptors in the hypothalamus. Fetissov, S.O., Kopp, J., Hökfelt, T. Neuropeptides (2004) [Pubmed]
  39. Okadaic acid induces interphase to mitotic-like microtubule dynamic instability by inactivating rescue. Gliksman, N.R., Parsons, S.F., Salmon, E.D. J. Cell Biol. (1992) [Pubmed]
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