Disease relevance of PPYR1

• In the present report, we demonstrate that hSNF5/INI1 binds to GADD34 in part through the PP1 docking site within a domain homologous to herpes simplex virus-1 ICP34 [1].
• These peptides also inhibited forskolin-stimulated adenylyl cyclase activity in Y4 receptor-expressing cells, and stimulated the binding of 35S-labeled GTP-gamma-S to pertussis toxin-sensitive G-proteins in particulates from these cells [2].
• In the present study, we examined the genetic and expression status of nine protein phosphatase 1 (PP1) genes in 55 human cancer cell lines, consisting of 10 small cell lung cancers, 22 non-small cell lung cancers, 11 colorectal cancers, 7 gastric cancers and 5 ovarian cancers [3].
• Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and production of vascular endothelial growth factor [4].
• BA-129, a specific Y4 receptor agonist, has growth inhibitory effects on pancreatic cancer in vitro [4].

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

• The human genes, PPYR1 and NPY5R, have been localized to chromosomes 10q and 4q, respectively, by analysis of a panel of rodent-human somatic cell hybrids and yeast artificial chromosomes [13].
• Assignment of the Y4 receptor gene (PPYR1) to human chromosome 10q11.2 and mouse chromosome 14 [14].
• The PP1 receptor has 46% overall amino acid sequence identity to the rat Y1 receptor and 56% identity in the transmembrane regions [15].
• Thus the hypothalamic NPY receptor mediating increases in plasma ACTH has a fragment activation profile unlike the Y1-Y4 or Y6 receptors and appears distinct from the NPY receptor controlling food intake [16].
• Thus, the sequence, the tissue distribution, and the binding profile of the PP1 receptor differ considerably between rat and human [15].

Anatomical context of PPYR1

• In stably transfected CHO cells, the PP1 receptor inhibits forskolin-stimulated cAMP synthesis [15].
• Y4 mRNA was detected by reverse transcriptase-polymerase chain reaction in human brain, coronary artery, and ileum, suggesting potential roles for Y4 receptors in central nervous system, cardiovascular, and gastrointestinal function [17].
• 3) RT-PCR shows expression of Y1, Y2, Y4, and Y5 receptor mRNA by chromaffin cells; these receptors are functional, as various receptor specific agonists elicit an increase in intracellular calcium [18].
• (125)I-1229U91 bound to cell lines expressing the human Y1 and Y4 receptors with high affinity [19].
• Neuropeptide Y, Y1, Y2 and Y4 receptors mediate Y agonist responses in isolated human colon mucosa [20].

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].

References