Biosynthesis, trafficking, and secretion of pro-opiomelanocortin-derived peptides

Journal of Molecular Endocrinology

Volumn 56, Issue 4, 2016, Pages T77-T97

  Cawley, Niamh X ^a   Li, Zhaojin ^a   Loh, Y Peng ^a  

^a EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT   (United States)

Author keywords

Hypothalamuspituitary adrenal axis; POMC sorting; POMC derived peptide secretion; Prohormone processing enzymes; Vesicle trafficking

Indexed keywords

BETA LIPOTROPIN; CARBOXYPEPTIDASE H; CORTICOTROPIN; FURIN; MELANOCORTIN 4 RECEPTOR; PROOPIOMELANOCORTIN; PEPTIDE; PEPTIDE HORMONE; SERINE PROTEINASE;

AMIDATION; ARCUATE NUCLEUS; CELL MIGRATION; CELL SELECTION; CORTICOTROPIN RELEASE; ENDOCRINE CELL; EXOCYTOSIS; HORMONE RELEASE; HORMONE SYNTHESIS; HUMAN; HYPOTHALAMUS; INTRACELLULAR TRAFFICKING; MEMBRANE DEPOLARIZATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN ACETYLATION; PROTEIN GLYCOSYLATION; PROTEIN PROCESSING; REGULATED SECRETORY PATHWAY; REVIEW; RNA INTERFERENCE; SECRETORY GRANULE; SECRETORY PATHWAY; SECRETORY VESICLE; ACETYLATION; ANIMAL; CHEMISTRY; GENETICS; HYPOPHYSIS ADRENAL SYSTEM; HYPOTHALAMUS HYPOPHYSIS SYSTEM; METABOLISM; PROTEIN DEGRADATION; PROTEIN SYNTHESIS; PROTEIN TRANSPORT; STRUCTURE ACTIVITY RELATION;

ACETYLATION; ANIMALS; EXOCYTOSIS; HUMANS; HYPOTHALAMO-HYPOPHYSEAL SYSTEM; PEPTIDE HORMONES; PEPTIDES; PITUITARY-ADRENAL SYSTEM; PRO-OPIOMELANOCORTIN; PROPROTEIN CONVERTASES; PROTEIN BIOSYNTHESIS; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEIN TRANSPORT; PROTEOLYSIS; SECRETORY VESICLES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84973369506     PISSN: 09525041     EISSN: 14796813     Source Type: Journal    
DOI: 10.1530/JME-15-0323     Document Type: Review

References (177)

1. Aguilera G, Millan MA, Hauger RL & Catt KJ 1987 Corticotropinreleasing factor receptors: distribution and regulation in brain, pituitary, and peripheral tissues. Annals of the New York Academy of Sciences 512 48-66. (doi:10.1111/j.1749-6632.1987.tb24950.x)
2. Akil H, Shiomi H & Matthews J 1985 Induction of the intermediate pituitary by stress: synthesis and release of a nonopioid form of beta-endorphin. Science 227 424-426. (doi:10.1126/science.3155575)
3. Alessi NE, Khachaturian H, Watson S & Akil H 1983 Postnatal ontogeny of acetylated and non-acetylated B-endorphin in rat pituitary. Life Sciences 33 (Supplement 1) 57-60.
4. Alsters SI, Goldstone AP, Buxton JL, Zekavati A, Sosinsky A, Yiorkas AM, Holder S, Klaber RE, Bridges N, van Haelst MM, et al. 2015 Truncating homozygous mutation of Carboxypeptidase E (CPE) in a morbidly obese female with type 2 diabetes mellitus, intellectual disability and hypogonadotrophic hypogonadism. PLoS ONE 10 e0131417.
5. Anderson EJP, Çakir I, Carrington S, Cone RD, Ghamari-Langroudi M, Gillyard T, Gimenez LE & Litt M 2016 60 YEARS OF POMC: regulation of feeding and energy homeostasis by aMSH. Journal of Molecular Endocrinology 56 T157-T174. (doi:10.1530/JME-16-0014)
6. Antoni FA 1996 Mortyn Jones memorial lecture-1995. Calcium checks cyclic AMP-corticosteroid feedback in adenohypophysial corticotrophs. Journal of Neuroendocrinology 8 659-672. (doi:10.1111/j.1365-2826.1996.tb00703.x)
7. Aoki Y, Iwasaki Y, Katahira M, Oiso Y & Saito H 1997 Regulation of the rat proopiomelanocortin gene expression in AtT-20 cells. I: effects of the common secretagogues. Endocrinology 138 1923-1929. (doi:10.1210/endo.138.5.5121)
8. Arnaoutova I, Jackson CL, Al-Awar OS, Donaldson JG & Loh YP 2003 Recycling of Raft-associated prohormone sorting receptor carboxypeptidase E requires interaction with ARF6. Molecular Biology of the Cell 14 4448-4457. (doi:10.1091/mbc.E02-11-0758)
9. Azaryan AV, Wong M, Friedman TC, Cawley NX, Estivariz FE, Chen HC & Loh YP 1993 Purification and characterization of a paired basic residue-specific yeast aspartic protease encoded by the YAP3 gene. Similarity to the mammalian pro-opiomelanocortinconverting enzyme. Journal of Biological Chemistry 268 11968-11975.
10. Azaryan AV, Schiller MR & Hook VY 1995 Chromaffin granule aspartic proteinase processes recombinant proopiomelanocortin (POMC). Biochemical and Biophysical Research Communications 215 937-944. (doi:10.1006/bbrc.1995.2554)
11. Beaulieu M, Goldman ME, Miyazaki K, Frey EA, Eskay RL, Kebabian JW & Cote TE 1984 Bromocriptine-induced changes in the biochemistry, physiology, and histology of the intermediate lobe of the rat pituitary gland. Endocrinology 114 1871-1884. (doi:10.1210/endo-114-5-1871).
12. Benjannet S, Rondeau N, Paquet L, Boudreault A, Lazure C, Chretien M & Seidah NG 1993 Comparative biosynthesis, covalent posttranslational modifications and efficiency of prosegment cleavage of the prohormone convertases PC1 and PC2: glycosylation, sulphation and identification of the intracellular site of prosegment cleavage of PC1 and PC2. Biochemical Journal 294 735-743.
13. Bennett HP 1984 Isolation and characterization of the 1 to 49 aminoterminal sequence of pro-opiomelanocortin from bovine posterior pituitaries. Biochemical and Biophysical Research Communications 125 229-236. (doi:10.1016/S0006-291X(84)80358-7)
14. Bennett HP 1986 Biosynthetic fate of the amino-terminal fragment of pro-opiomelanocortin within the intermediate lobe of the mouse pituitary. Peptides 7 615-622. (doi:10.1016/0196-9781(86)90036-7)
15. Bennett HP, Seidah NG, Benjannet S, Solomon S & Chretien M 1986 Reinvestigation of the disulfide bridge arrangement in human proopiomelanocortin N-terminal segment (hNT 1-76). International Journal of Peptide and Protein Research 27 306-313.
16. Bergeron F, Sirois F & Mbikay M 2002 ACTH secretion by mouse corticotroph AtT20 cells is negatively modulated by the intracellular level of 7B2. FEBS Letters 512 259-262. (doi:10.1016/S0014-5793(02)02277-9).
17. Beuers U, Hertting G & Knepel W 1982 Release of beta-lipotropin-and beta-endorphin-like material induced by angiotensin in the conscious rat. British Journal of Pharmacology 76 579-585. (doi:10.1111/j.1476-5381.1982.tb09257.x)
18. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, et al. 2008 Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. Journal of Clinical Endocrinology & Metabolism 93 2454-2462.
19. Bonnemaison ML, Eipper BA & Mains RE 2013 Role of adaptor proteins in secretory granule biogenesis and maturation. Frontiers in Endocrinology 4 101.
20. Bowman ME, Robinson PJ & Smith R 1997 Atrial natriuretic peptide, cyclic GMP analogues and modulation of guanylyl cyclase do not alter stimulated POMC peptide release from perifused rat or sheep corticotrophs. Journal of Neuroendocrinology 9 929-936. (doi:10.1046/ j.1365-2826.1997.00665.x).
21. Burgess TL & Kelly RB 1984 Sorting and secretion of adrenocorticotropin in a pituitary tumor cell line after perturbation of the level of a secretory granule-specific proteoglycan. Journal of Cell Biology 99 2223-2230. (doi:10.1083/jcb.99.6.2223)
22. Burgess TL & Kelly RB 1987 Constitutive and regulated secretion of proteins. Annual Review of Cell Biology 3 243-293. (doi:10.1146/ annurev.cb.03.110187.001331).
23. Burgess TL, Craik CS & Kelly RB 1985 The exocrine protein trypsinogen is targeted into the secretory granules of an endocrine cell line: studies by gene transfer. Journal of Cell Biology 101 639-645. (doi:10.1083/jcb.101.2.639)
24. Castro MG, Birch NP & Loh YP 1989 Regulated secretion of pro-opiomelanocortin converting enzyme and an aminopeptidase B-like enzyme from dispersed bovine intermediate lobe pituitary cells. Journal of Neurochemistry 52 1619-1628. (doi:10.1111/j.1471-4159.1989.tb09217.x)
25. Cawley NX, Pu LP & Loh YP 1996 Immunological identification and localization of yeast aspartic protease 3-like prohormone-processing enzymes in mammalian brain and pituitary. Endocrinology 137 5135-5143.
26. Cawley NX, Normant E, Chen A & Loh YP 2000 Oligomerization of proopiomelanocortin is independent of pH, calcium and the sorting signal for the regulated secretory pathway. FEBS Letters 481 37-41. (doi:10.1016/S0014-5793(00)01961-X)
27. Cawley NX, Rodriguez YM, Maldonado A & Loh YP 2003 Trafficking of mutant carboxypeptidase E to secretory granules in a beta-cell line derived from Cpe(fat)/Cpe(fat) mice. Endocrinology 144 292-298. (doi:10.1210/en.2002-220588)
28. Cawley NX, Zhou J, Hill JM, Abebe D, Romboz S, Yanik T, Rodriguiz RM, Wetsel WC & Loh YP 2004 The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits. Endocrinology 145 5807-5819. (doi:10.1210/en.2004-0847)
29. Cawley NX, Yanik T, Woronowicz A, Chang W, Marini JC & Loh YP 2010 Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density. American Journal of Physiology: Endocrinology and Metabolism 299 E189-E197.
30. Cawley NX, Portela-Gomes G, Lou H & Loh YP 2011 Yapsin 1 immunoreactivity in {alpha}-cells of human pancreatic islets: implications for the processing of human proglucagon by mammalian aspartic proteases. Journal of Endocrinology 210 181-187. (doi:10.1530/JOE-11-0121)
31. Cawley NX, Wetsel WC, Murthy SR, Park JJ, Pacak K & Loh YP 2012 New roles of carboxypeptidase E in endocrine and neural function and cancer. Endocrine Reviews 33 216-253. (doi:10.1210/er.2011-1039)
32. Cawley NX, Rathod T, Young S, Lou H, Birch N & Loh YP 2015 Carboxypeptidase E and Secretogranin III coordinately facilitate efficient sorting of pro-opiomelanocortin to the regulated secretory pathway in AtT20 cells. Molecular Endocrinology 30 37-47. (doi:10.1210/me.2015-1166)
33. Chan JS, Lu CL, Seidah NG & Chretien M 1982 Corticotropin releasing factor (CRF): effects on the release of pro-opiomelanocortin (POMC)-related peptides by human anterior pituitary cells in vitro. Endocrinology 111 1388-1390. (doi:10.1210/endo-111-4-1388)
34. Chanat E & Huttner WB 1991 Milieu-induced, selective aggregation of regulated secretory proteins in the trans-Golgi network. Journal of Cell Biology 115 1505-1519. (doi:10.1083/jcb.115.6.1505)
35. Chandra S, Kable EP, Morrison GH & Webb WW 1991 Calcium sequestration in the Golgi apparatus of cultured mammalian cells revealed by laser scanning confocal microscopy and ion microscopy. Journal of Cell Science 100 747-752.
36. Chappell MC, Loh YP & O'Donohue TL 1982 Evidence for an opiomelanotropin acetyltransferase in the rat pituitary neurointermediate lobe. Peptides 3 405-410. (doi:10.1016/0196-9781(82)90100-0).
37. Che FY, Biswas R & Fricker LD 2005 Relative quantitation of peptides in wild-type and Cpe(fat/fat) mouse pituitary using stable isotopic tags and mass spectrometry. Journal of Mass Spectrometry 40 227-237. (doi:10.1002/jms.742)
38. Chretien M & Mbikay M 2016 60 YEARS OF POMC: From the prohormone theory to proopiomelanocortin and to proprotein convertases (PCSK1 to PCSK9). Journal of Molecular Endocrinology T49-T62. (doi:10.1530/JME-15-0261)
39. Colomer V, Kicska GA & Rindler MJ 1996 Secretory granule content proteins and the luminal domains of granule membrane proteins aggregate in vitro at mildly acidic pH. Journal of Biological Chemistry 271 48-55. (doi:10.1074/jbc.271.1.48)
40. Cool DR & Loh YP 1994 Identification of a sorting signal for the regulated secretory pathway at the N-terminus of pro-opiomelanocortin. Biochimie 76 265-270. (doi:10.1016/0300-9084(94)90156-2).
41. Cool DR & Loh YP 1998 Carboxypeptidase E is a sorting receptor for prohormones: binding and kinetic studies. Molecular and Cellular Endocrinology 139 7-13. (doi:10.1016/S0303-7207(98)00081-1)
42. Cool DR, Fenger M, Snell CR & Loh YP 1995 Identification of the sorting signal motif within pro-opiomelanocortin for the regulated secretory pathway. Journal of Biological Chemistry 270 8723-8729. (doi:10.1074/jbc.270.15.8723)
43. Cool DR, Normant E, Shen F, Chen HC, Pannell L, Zhang Y & Loh YP 1997 Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88 73-83. (doi:10.1016/S0092-8674(00)81860-7)
44. Costa G, Saija A, Padovano I, Trimarchi GR, De Pasquale R & Caputi AP 1984 The calcium antagonist nimodipine increases beta-endorphin release from rat hypophysis through an action on adrenal glands. An 'in vivo' and 'in vitro' study. Pharmacological Research Communications 16 959-968. (doi:10.1016/S0031-6989(84)80060-0)
45. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD & Low MJ 2001 Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411 480-484. (doi:10.1038/35078085)
46. Crine P, Gianoulakis C, Seidah NG, Gossard F, Pezalla PD, Lis M & Chretien M 1978 Biosynthesis of beta-endorphin from betalipotropin and a larger molecular weight precursor in rat pars intermedia. PNAS 75 4719-4723. (doi:10.1073/pnas.75.10.4719)
47. Crine P, Gossard F, Seidah NG, Blanchette L, Lis M & Chretien M 1979 Concomitant synthesis of beta-endorphin and alpha-melanotropin from two forms of pro-opiomelanocortin in the rat pars intermedia. PNAS 76 5085-5089. (doi:10.1073/pnas.76.10.5085)
48. Deakin JF, Dostrovsky JO & Smyth DG 1980 Influence of N-terminal acetylation and C-terminal proteolysis on the analgesic activity of beta-endorphin. Biochemical Journal 189 501-506. (doi:10.1042/ bj1890501).
49. Devi L 1992 Secretion and regulation of a neuropeptide-processing enzyme by AtT-20 cells. Endocrinology 131 1930-1935.
50. Dhanvantari S, Arnaoutova I, Snell CR, Steinbach PJ, Hammond K, Caputo GA, London E & Loh YP 2002 Carboxypeptidase E, a prohormone sorting receptor, is anchored to secretory granules via a C-terminal transmembrane insertion. Biochemistry 41 52-60. (doi:10.1021/bi015698n)
51. Dhanvantari S, Shen FS, Adams T, Snell CR, Zhang C, Mackin RB, Morris SJ & Loh YP 2003 Disruption of a receptor-mediated mechanism for intracellular sorting of proinsulin in familial hyperproinsulinemia. Molecular Endocrinology 17 1856-1867. (doi:10.1210/me.2002-0380)
52. Dyken JJ & Sambanis A 1994 Ammonium selectively inhibits the regulated pathway of protein secretion in two endocrine cell lines. Enzyme and Microbial Technology 16 90-98.
53. Egel-Mitani M, Flygenring HP & Hansen MT 1990 A novel aspartyl protease allowing KEX2-independent MF alpha propheromone processing in yeast. Yeast 6 127-137. (doi:10.1002/yea.320060206)
54. Estivariz FE, Friedman TC, Chikuma T & Loh YP 1992 Processing of adrenocorticotropin by two proteases in bovine intermediate lobe secretory vesicle membranes. A distinct acidic, tetrabasic residuespecific calcium-activated serine protease and a PC2-like enzyme. Journal of Biological Chemistry 267 7456-7463.
55. Fagarasan MO, Eskay R & Axelrod J 1989 Interleukin 1 potentiates the secretion of beta-endorphin induced by secretagogues in a mouse pituitary cell line (AtT-20). PNAS 86 2070-2073. (doi:10.1073/ pnas.86.6.2070).
56. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E, Keogh J, O'Rahilly S & Creemers JW 2007 Hyperphagia and earlyonset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. Journal of Clinical Endocrinology & Metabolism 92 3369-3373.
57. Fischer JL & Moriarty CM 1977 Control of bioactive corticotropin release from the neuro-intermediate lobe of the rat pituitary in vitro. Endocrinology 100 1047-1054. (doi:10.1210/endo-100-4-1047)
58. Fortenberry Y, Liu J & Lindberg I 1999 The role of the 7B2 CT peptide in the inhibition of prohormone convertase 2 in endocrine cell lines. Journal of Neurochemistry 73 994-1003. (doi:10.1046/j.1471-4159.1999.0730994.x)
59. Fricker LD & Snyder SH 1982 Enkephalin convertase: purification and characterization of a specific enkephalin-synthesizing carboxypeptidase localized to adrenal chromaffin granules. PNAS 79 3886-3890. (doi:10.1073/pnas.79.12.3886)
60. Fricker LD, McKinzie AA, Sun J, Curran E, Qian Y, Yan L, Patterson SD, Courchesne PL, Richards B, Levin N, et al. 2000 Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing. Journal of Neuroscience 20 639-648.
61. Friedman TC, Loh YP & Birch NP 1994 In vitro processing of proopiomelanocortin by recombinant PC1 (SPC3). Endocrinology 135 854-862.
62. Friedman TC, Cool DR, Jayasvasti V, Louie D & Loh YP 1996 Processing of pro-opiomelanocortin in GH3 cells: inhibition by prohormone convertase 2 (PC2) antisense mRNA. Molecular and Cellular Endocrinology 116 89-96. (doi:10.1016/0303-7207(95)03702-0)
63. Furuta M, Yano H, Zhou A, Rouille Y, Holst JJ, Carroll R, Ravazzola M, Orci L, Furuta H & Steiner DF 1997 Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. PNAS 94 6646-6651. (doi:10.1073/ pnas.94.13.6646).
64. Gainer H, Russell JT & Loh YP 1984 An aminopeptidase activity in bovine pituitary secretory vesicles that cleaves the N-terminal arginine from beta-lipotropin60-65. FEBS Letters 175 135-139. (doi:10.1016/0014-5793(84)80586-4)
65. Gibson TR & Glembotski CC 1985 Acetylation of alpha MSH and betaendorphin by rat neurointermediate pituitary secretory granuleassociated acetyltransferase. Peptides 6 615-620. (doi:10.1016/0196-9781(85)90162-7)
66. Glembotski CC 1982 Characterization of the peptide acetyltransferase activity in bovine and rat intermediate pituitaries responsible for the acetylation of beta-endorphin and alpha-melanotropin. Journal of Biological Chemistry 257 10501-10509.
67. Goodman LJ & Gorman CM 1994 Autoproteolytic activation of the mouse prohormone convertase mPC1. Biochemical and Biophysical Research Communications 201 795-804. (doi:10.1006/ bbrc.1994.1771).
68. Gumbiner B & Kelly RB 1981 Secretory granules of an anterior pituitary cell line, AtT-20, contain only mature forms of corticotropin and beta-lipotropin. PNAS 78 318-322.
69. Gumbiner B & Kelly RB 1982 Two distinct intracellular pathways transport secretory and membrane glycoproteins to the surface of pituitary tumor cells. Cell 28 51-59. (doi:10.1016/0092-8674(82)90374-9).
70. Guttmann S & Boissonnas RA 1961 Influence of the structure of the n-terminal extremity of alpha-MSH on the melanophore stimulating activity of this hormone. Experientia 17 265-267. (doi:10.1007/ BF02161433).
71. Ham J & Smyth DG 1984 Regulation of bioactive beta-endorphin processing in rat pars intermedia. FEBS Letters 175 407-411. (doi:10.1016/0014-5793(84)80778-4)
72. Hollt V & Bergmann M 1982 Effects of acute and chronic haloperidol treatment on the concentrations of immunoreactive beta-endorphin in plasma, pituitary and brain of rats. Neuropharmacology 21 147-154. (doi:10.1016/0028-3908(82)90154-X)
73. Hook VY 1985 Differential distribution of carboxypeptidase-processing enzyme activity and immunoreactivity in membrane and soluble components of chromaffin granules. Journal of Neurochemistry 45 987-989. (doi:10.1111/j.1471-4159.1985.tb04094.x)
74. Hook VY & Loh YP 1984 Carboxypeptidase B-like converting enzyme activity in secretory granules of rat pituitary. PNAS 81 2776-2780. (doi:10.1073/pnas.81.9.2776)
75. Hook VY, Eiden LE & Brownstein MJ 1982a A carboxypeptidase processing enzyme for enkephalin precursors. Nature 295 341-342.
76. Hook VY, Heisler S & Axelrod J 1982b Corticotropin-releasing factor stimulates phospholipid methylation and corticotropin secretion in mouse pituitary tumor cells. PNAS 79 6220-6224.
77. Hosaka M, Watanabe T, Sakai Y, Uchiyama Y & Takeuchi T 2002 Identification of a chromogranin A domain that mediates binding to secretogranin III and targeting to secretory granules in pituitary cells and pancreatic beta-cells. Molecular Biology of the Cell 13 3388-3399. (doi:10.1091/mbc.02-03-0040)
78. Hosaka M, Suda M, Sakai Y, Izumi T, Watanabe T & Takeuchi T 2004 Secretogranin III binds to cholesterol in the secretory granule membrane as an adapter for chromogranin A. Journal of Biological Chemistry 279 3627-3634.
79. Hosaka M, Watanabe T, Sakai Y, Kato T & Takeuchi T 2005 Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules. Journal of Cell Science 118 4785-4795. (doi:10.1242/jcs.02608)
80. Imura H 1985 ACTH and related peptides: molecular biology, biochemistry and regulation of secretion. Clinical Endocrinology & Metabolism 14 845-866.
81. Invitti C, Pecori Giraldi F, Dubini A, Piolini M & Cavagnini F 1991 Effect of sandostatin on CRF-stimulated secretion of ACTH, betalipotropin and beta-endorphin. Hormone and Metabolic Research 23 233-235. (doi:10.1055/s-2007-1003660)
82. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC & O'Rahilly S 1997 Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genetics 16 303-306. (doi:10.1038/ng0797-303)
83. Jackson RS, O'Rahilly S, Brain C & Nussey SS 1999 Proopiomelanocortin products and human early-onset obesity. Journal of Clinical Endocrinology & Metabolism 84 819-820.
84. Jain RK, Chang WT, Geetha C, Joyce PB & Gorr SU 2002 In vitro aggregation of the regulated secretory protein chromogranin A. Biochemical Journal 368 605-610. (doi:10.1042/bj20021195)
85. Joshi D, Miller MM, Seidah NG & Day R 1995 Age-related alterations in the expression of prohormone convertase messenger ribonucleic acid (mRNA) levels in hypothalamic proopiomelanocortin mRNA neurons in the female C57BL/ 6J mouse. Endocrinology 136 2721-2729.
86. Kanmera T & Chaiken IM 1985 Pituitary enzyme conversion of putative synthetic oxytocin precursor intermediates. Journal of Biological Chemistry 260 10118-10124.
87. Kelly RB 1985 Pathways of protein secretion in eukaryotes. Science 230 25-32. (doi:10.1126/science.2994224)
88. Kemppainen RJ & Behrend EN 2010 Acute inhibition of carboxypeptidase E expression in AtT-20 cells does not affect regulated secretion of ACTH. Regulatory Peptides 165 174-179. (doi:10.1016/j.regpep.2010.07.162)
89. Kemppainen RJ, Zerbe CA & Sartin JL 1989 Regulation and secretion of proopiomelanocortin peptides from isolated perifused dog pituitary pars intermedia cells. Endocrinology 124 2208-2217. (doi:10.1210/ endo-124-5-2208).
90. Knepel W & Gerhards C 1987 Stimulation by melittin of adrenocorticotropin and beta-endorphin release from rat adenohypophysis in vitro. Prostaglandins 33 479-490. (doi:10.1016/0090-6980(87)90027-X)
91. Kogel T & Gerdes HH 2010 Maturation of secretory granules. Results and Problems in Cell Differentiation 50 1-20.
92. Kreis TE, Matteoni R, Hollinshead M & Tooze J 1989 Secretory granules and endosomes show saltatory movement biased to the anterograde and retrograde directions, respectively, along microtubules in AtT20 cells. European Journal of Cell Biology 49 128-139.
93. Krude H, Biebermann H, Luck W, Horn R, Brabant G & Gruters A 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genetics 19 155-157. (doi:10.1038/509)
94. Kumar D, Mains RE & Eipper E 2015 60 YEARS OF POMC: From POMC and alphaMSH to PAM, molecular oxygen, copper and vitamin C. Journal of Molecular Endocrinology T63-T76. (doi:10.1530/JME-15-0266).
95. Lee SN, Prodhomme E & Lindberg I 2004 Prohormone convertase 1 (PC1) processing and sorting: effect of PC1 propeptide and proSAAS. Journal of Endocrinology 182 353-364. (doi:10.1677/joe.0.1820353)
96. Lin WJ & Salton SR 2013 The regulated secretory pathway and human disease: insights from gene variants and single nucleotide polymorphisms. Frontiers in Endocrinology 4 96.
97. Lindberg I, van den Hurk WH, Bui C & Batie CJ 1995 Enzymatic characterization of immunopurified prohormone convertase 2: potent inhibition by a 7B2 peptide fragment. Biochemistry 34 5486-5493. (doi:10.1021/bi00016a020)
98. Liotta AS, Loudes C, McKelvy JF & Krieger DT 1980 Biosynthesis of precursor corticotropin/endorphin-, corticotropin-, alphamelanotropin-, beta-lipotropin-, and beta-endorphin-like material by cultured neonatal rat hypothalamic neurons. PNAS 77 1880-1884. (doi:10.1073/pnas.77.4.1880)
99. Loh YP 1979 Immunological evidence for two common precursors to corticotropins, endorphins, and melanotropin in the neurointermediate lobe of the toad pituitary. PNAS 76 796-800. (doi:10.1073/pnas.76.2.796)
100. Loh YP & Tam WW 1985 Association of newly synthesized proopiomelanocortin with secretory granule membranes in pituitary pars intermedia cells. FEBS Letters 184 40-43. (doi:10.1016/0014-5793(85)80648-7).
101. Loh YP, Tam WW & Russell JT 1984 Measurement of delta pH and membrane potential in secretory vesicles isolated from bovine pituitary intermediate lobe. Journal of Biological Chemistry 259 8238-8245.
102. Loh YP, Parish DC & Tuteja R 1985 Purification and characterization of a paired basic residue-specific pro-opiomelanocortin converting enzyme from bovine pituitary intermediate lobe secretory vesicles. Journal of Biological Chemistry 260 7194-7205.
103. Loh YP, Snell CR & Cool DR 1997 Receptor-mediated targeting of hormones to secretory granules: role of carboxypeptidase E. Trends in Endocrinology & Metabolism 8 130-137.
104. Loh YP, Maldonado A, Zhang C, Tam WH & Cawley N 2002 Mechanism of sorting proopiomelanocortin and proenkephalin to the regulated secretory pathway of neuroendocrine cells. Annals of the New York Academy of Sciences 971 416-425. (doi:10.1111/j.1749-6632.2002.tb04504.x).
105. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, et al. 2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics 40 768-775.
106. Lou H, Kim SK, Zaitsev E, Snell CR, Lu B & Loh YP 2005 Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase E. Neuron 45 245-255. (doi:10.1016/j.neuron.2004.12.037)
107. Lou H, Park JJ, Cawley NX, Sarcon A, Sun L, Adams T & Loh YP 2010 Carboxypeptidase E cytoplasmic tail mediates localization of synaptic vesicles to the pre-active zone in hypothalamic pre-synaptic terminals. Journal of Neurochemistry 114 886-896. (doi:10.1111/j.1471-4159.2010.06820.x)
108. Lou H, Park JJ, Phillips A & Loh YP 2013 gamma-Adducin promotes process outgrowth and secretory protein exit from the Golgi apparatus. Journal of Molecular Neuroscience 49 1-10. (doi:10.1007/ s12031-012-9827-0).
109. Lowry P 2015 60 YEARS OF POMC: Purification and biological characterisation of melanotrophins and corticotrophins. Journal of Molecular Endocrinology.
110. Mains RE & Eipper BA 1976 Biosynthesis of adrenocorticotropic hormone in mouse pituitary tumor cells. Journal of Biological Chemistry 251 4115-4120.
111. Mains RE & Eipper BA 1979 Synthesis and secretion of corticotropins, melanotropins, and endorphins by rat intermediate pituitary cells. Journal of Biological Chemistry 254 7885-7894.
112. Mains RE & Eipper BA 1981a Coordinate, equimolar secretion of smaller peptide products derived from pro-ACTH/endorphin by mouse pituitary tumor cells. Journal of Cell Biology 89 21-28.
113. Mains RE & Eipper BA 1981b Differences in the post-translational processing of beta-endorphin in rat anterior and intermediate pituitary. Journal of Biological Chemistry 256 5683-5688.
114. Mains RE, Eipper BA & Ling N 1977 Common precursor to corticotropins and endorphins. PNAS 74 3014-3018.
115. Mbikay M, Seidah NG & Chretien M 2001 Neuroendocrine secretory protein 7B2: structure, expression and functions. Biochemical Journal 357 329-342. (doi:10.1042/bj3570329)
116. McNicol AM 1986 A study of intermediate lobe differentiation in the human pituitary gland. Journal of Pathology 150 169-173. (doi:10.1002/path.1711500304)
117. Millington WR, O'Donohue TL, Chappell MC, Roberts JL & Mueller GP 1986 Coordinate regulation of peptide acetyltransferase activity and proopiomelanocortin gene expression in the intermediate lobe of the rat pituitary. Endocrinology 118 2024-2033. (doi:10.1210/ endo-118-5-2024).
118. Moore HP & Kelly RB 1985 Secretory protein targeting in a pituitary cell line: differential transport of foreign secretory proteins to distinct secretory pathways. Journal of Cell Biology 101 1773-1781. (doi:10.1083/jcb.101.5.1773)
119. Moore HH & Kelly RB 1986 Re-routing of a secretory protein by fusion with human growth hormone sequences. Nature 321 443-446. (doi:10.1038/321443a0)
120. Moore HP, Gumbiner B & Kelly RB 1983a Chloroquine diverts ACTH from a regulated to a constitutive secretory pathway in AtT-20 cells. Nature 302 434-436.
121. Moore HP, Gumbiner B & Kelly RB 1983b A subclass of proteins and sulfated macromolecules secreted by AtT-20 (mouse pituitary tumor) cells is sorted with adrenocorticotropin into dense secretory granules. Journal of Cell Biology 97 810-817.
122. Moore HP, Walker MD, Lee F & Kelly RB 1983c Expressing a human proinsulin cDNA in a mouse ACTH-secreting cell. Intracellular storage, proteolytic processing, and secretion on stimulation. Cell 35 531-538.
123. Muller L, Zhu X & Lindberg I 1997 Mechanism of the facilitation of PC2 maturation by 7B2: involvement in ProPC2 transport and activation but not folding. Journal of Cell Biology 139 625-638. (doi:10.1083/ jcb.139.3.625).
124. Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ & Leiter EH 1995 Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genetics 10 135-142. (doi:10.1038/ng0695-135)
125. Nakanishi S, Inoue A, Kita T, Nakamura M, Chang AC, Cohen SN & Numa S 1979 Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature 278 423-427. (doi:10.1038/278423a0)
126. Normant E & Loh YP 1998 Depletion of carboxypeptidase E, a regulated secretory pathway sorting receptor, causes misrouting and constitutive secretion of proinsulin and proenkephalin, but not chromogranin A. Endocrinology 139 2137-2145. (doi:10.1210/ endo.139.4.5951).
127. Paquet L, Zhou A, Chang EY & Mains RE 1996 Peptide biosynthetic processing: distinguishing prohormone convertases PC1 and PC2. Molecular and Cellular Endocrinology 120 161-168. (doi:10.1016/ 0303-7207(96)03834-8).
128. Park JJ, Cawley NX & Loh YP 2008 Carboxypeptidase E cytoplasmic taildriven vesicle transport is key for activity-dependent secretion of peptide hormones. Molecular Endocrinology 22 989-1005. (doi:10.1210/me.2007-0473)
129. Pepper DJ & Bicknell AB 2009 The stimulation of mitogenic signaling pathways by N-POMC peptides. Molecular and Cellular Endocrinology 300 77-82. (doi:10.1016/j.mce.2008.09.021)
130. Petraglia F, Cella SG, Radice L, Genazzani AR & Muller EE 1986 gamma-Aminobutyric acid inhibits beta-endorphin secretion from the anterior pituitary but not the neurointermediate lobe in the rat. Endocrinology 118 360-366. (doi:10.1210/endo-118-1-360).
131. Plum L, Lin HV, Dutia R, Tanaka J, Aizawa KS, Matsumoto M, Kim AJ, Cawley NX, Paik JH, Loh YP, et al. 2009 The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic proopiomelanocortin neurons with regulation of food intake. Nature Medicine 15 1195-1201. (doi:10.1038/nm.2026)
132. Qian Y, Devi LA, Mzhavia N, Munzer S, Seidah NG & Fricker LD 2000 The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1. Journal of Biological Chemistry 275 23596-23601. (doi:10.1074/jbc.M001583200)
133. Rindler MJ 1998 Carboxypeptidase E, a peripheral membrane protein implicated in the targeting of hormones to secretory granules, co-aggregates with granule content proteins at acidic pH. Journal of Biological Chemistry 273 31180-31185.
134. Sabol SL 1980 Storage and secretion of beta-endorphin and related peptides by mouse pituitary tumor cells: regulation by glucocorticoids. Archives of Biochemistry and Biophysics 203 37-48. (doi:10.1016/0003-9861(80)90151-4)
135. Sapun-Malcolm D, Farah JM Jr & Mueller GP 1983 Evidence for serotonergic stimulation of pituitary beta-endorphin release: preferential release from the anterior lobe in vivo. Life Sciences 33 95-102. (doi:10.1016/0024-3205(83)90716-6)
136. Scholey JM 2013 Kinesin-2: a family of heterotrimeric and homodimeric motors with diverse intracellular transport functions. Annual Review of Cell and Developmental Biology 29 443-469. (doi:10.1146/ annurev-cellbio-101512-122335).
137. Scott AP & Lowry PJ 1974 Adrenocorticotrophic and melanocytestimulating peptides in the human pituitary. Biochemical Journal 139 593-602. (doi:10.1042/bj1390593)
138. Seger MA & Bennett HP 1986 Structure and bioactivity of the amino-terminal fragment of pro-opiomelanocortin. Journal of Steroid Biochemistry 25 703-710. (doi:10.1016/ 0022-4731(86)90298-0).
139. Seidah NG 2011 The proprotein convertases, 20 years later. Methods in Molecular Biology 768 23-57. (doi:10.1007/978-1-61779-204-5_3).
140. Seidah NG, Marcinkiewicz M, Benjannet S, Gaspar L, Beaubien G, Mattei MG, Lazure C, Mbikay M & Chretien M 1991 Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Molecular Endocrinology 5 111-122. (doi:10.1210/ mend-5-1-111).
141. Seksek O, Biwersi J & Verkman AS 1995 Direct measurement of trans-Golgi pH in living cells and regulation by second messengers. Journal of Biological Chemistry 270 4967-4970. (doi:10.1074/ jbc.270.10.4967).
142. Shen FS & Loh YP 1997 Intracellular misrouting and abnormal secretion of adrenocorticotropin and growth hormone in cpefat mice associated with a carboxypeptidase E mutation. PNAS 94 5314-5319. (doi:10.1073/pnas.94.10.5314)
143. Shen FS, Aguilera G & Loh YP 1999 Altered biosynthesis and secretion of pro-opiomelanocortin in the intermediate and anterior pituitary of carboxypeptidase E-deficient, Cpe(fat)/Cpe(fat)mice. Neuropeptides 33 276-280. (doi:10.1054/npep.1999.0045)
144. Sheppard KE 1995 Cyclosporin A and FK506 are potent activators of proopiomelanocortin-derived peptide secretion without affecting corticotrope glucocorticoid receptor function. Journal of Neuroendocrinology 7 833-840. (doi:10.1111/j.1365-2826.1995.tb00723.x).
145. Shibasaki T & Masui H 1982 Effects of various neuropeptides on the secretion of proopiomelanocortin-derived peptides by a cultured pituitary adenoma causing Nelson's syndrome. Journal of Clinical Endocrinology & Metabolism 55 872-876.
146. Shibasaki T, Naruse M, Yamauchi N, Masuda A, Imaki T, Naruse K, Demura H, Ling N, Inagami T & Shizume K 1986 Rat atrial natriuretic factor suppresses proopiomelanocortin-derived peptides secretion from both anterior and intermediate lobe cells and growth hormone release from anterior lobe cells of rat pituitary in vitro. Biochemical and Biophysical Research Communications 135 1035-1041. (doi:10.1016/0006-291X(86)91032-6)
147. Shin MS, Chang H, Namkoong C, Kang GM, Kim HK, Gil SY, Yu JH, Park KH & Kim MS 2013 Hypothalamic and pituitary clusterin modulates neurohormonal responses to stress. Neuroendocrinology 98 233-241. (doi:10.1159/000355625)
148. Shiver T, Familari M & Aguilera G 1992 Regulation of intermediate pituitary corticotropin-releasing hormone receptors by dopamine. Endocrinology 130 2299-2304.
149. Sly WS & Fischer HD 1982 The phosphomannosyl recognition system for intracellular and intercellular transport of lysosomal enzymes. Journal of Cellular Biochemistry 18 67-85. (doi:10.1002/ jcb.1982.240180107).
150. Srinivasan S, Bunch DO, Feng Y, Rodriguiz RM, Li M, Ravenell RL, Luo GX, Arimura A, Fricker LD, Eddy EM, et al. 2004 Deficits in reproduction and pro-gonadotropin-releasing hormone processing in male Cpefat mice. Endocrinology 145 2023-2034. (doi:10.1210/ en.2003-1442).
151. Stevens A & White A 2010 ACTH: cellular peptide hormone synthesis and secretory pathways. Results and Problems in Cell Differentiation 50 63-84.
152. Sun M, Watanabe T, Bochimoto H, Sakai Y, Torii S, Takeuchi T & Hosaka M 2013 Multiple sorting systems for secretory granules ensure the regulated secretion of peptide hormones. Traffic 14 205-218. (doi:10.1111/tra.12029)
153. Surprenant A 1982 Correlation between electrical activity and ACTH/ beta-endorphin secretion in mouse pituitary tumor cells. Journal of Cell Biology 95 559-566. (doi:10.1083/jcb.95.2.559)
154. Swanson LW, Sawchenko PE, Rivier J & Vale WW 1983 Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 36 165-186. (doi:10.1159/000123454)
155. Tam WW, Andreasson KI & Loh YP 1993 The amino-terminal sequence of pro-opiomelanocortin directs intracellular targeting to the regulated secretory pathway. European Journal of Cell Biology 62 294-306.
156. Thomas L, Leduc R, Thorne BA, Smeekens SP, Steiner DF & Thomas G 1991 Kex2-like endoproteases PC2 and PC3 accurately cleave a model prohormone in mammalian cells: evidence for a common core of neuroendocrine processing enzymes. PNAS 88 5297-5301. (doi:10.1073/pnas.88.12.5297)
157. Tilders FJ, Post M, Jackson S, Lowry PJ & Smelik PG 1981 beta-Adrenergic stimulation of the release of ACTH-and LPH-related peptides from the pars intermedia of the rat pituitary gland. Acta Endocrinologica 97 343-351.
158. Tomiko SA, Taraskevich PS & Douglas WW 1983 GABA acts directly on cells of pituitary pars intermedia to alter hormone output. Nature 301 706-707. (doi:10.1038/301706a0)
159. Tooze J & Burke B 1987 Accumulation of adrenocorticotropin secretory granules in the midbody of telophase AtT20 cells: evidence that secretory granules move anterogradely along microtubules. Journal of Cell Biology 104 1047-1057. (doi:10.1083/jcb.104.4.1047)
160. Tooze J & Tooze SA 1986 Clathrin-coated vesicular transport of secretory proteins during the formation of ACTH-containing secretory granules in AtT20 cells. Journal of Cell Biology 103 839-850. (doi:10.1083/jcb.103.3.839)
161. Tooze J, Hollinshead M, Frank R & Burke B 1987a An antibody specific for an endoproteolytic cleavage site provides evidence that proopiomelanocortin is packaged into secretory granules in AtT20 cells before its cleavage. Journal of Cell Biology 105 155-162.
162. Tooze J, Tooze SA & Fuller SD 1987b Sorting of progeny coronavirus from condensed secretory proteins at the exit from the trans-Golgi network of AtT20 cells. Journal of Cell Biology 105 1215-1226.
163. Tran TN, Fryer JN, Lederis K & Vaudry H 1990 CRF, urotensin I, and sauvagine stimulate the release of POMC-derived peptides from goldfish neurointermediate lobe cells. General and Comparative Endocrinology 78 351-360. (doi:10.1016/0016-6480(90)90025-H)
164. Tsukamoto N, Otsuka F, Miyoshi T, Yamanaka R, Inagaki K, Yamashita M, Otani H, Takeda M, Suzuki J, Ogura T, et al. 2010 Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells: involvement of up-regulation of BMP receptor signaling by somatostatin analogs. Endocrinology 151 1129-1141. (doi:10.1210/en.2009-1102)
165. Tsukamoto N, Otsuka F, Ogura-Ochi K, Inagaki K, Nakamura E, Toma K, Terasaka T, Iwasaki Y & Makino H 2013 Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells. Molecular and Cellular Endocrinology 375 1-9. (doi:10.1016/j.mce.2013.05.010)
166. Varlamov O, Fricker LD, Furukawa H, Steiner DF, Langley SH & Leiter EH 1997 Beta-cell lines derived from transgenic Cpe(fat)/ Cpe(fat) mice are defective in carboxypeptidase E and proinsulin processing. Endocrinology 138 4883-4892.
167. Wardlaw SL 2011 Hypothalamic proopiomelanocortin processing and the regulation of energy balance. European Journal of Pharmacology 660 213-219. (doi:10.1016/j.ejphar.2010.10.107)
168. Wardman JH, Zhang X, Gagnon S, Castro LM, Zhu X, Steiner DF, Day R & Fricker LD 2010 Analysis of peptides in prohormone convertase 1/3 null mouse brain using quantitative peptidomics. Journal of Neurochemistry 114 215-225.
169. Yaswen L, Diehl N, Brennan MB & Hochgeschwender U 1999 Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Medicine 5 1066-1070. (doi:10.1038/12506)
170. Zhang CF, Snell CR & Loh YP 1999 Identification of a novel prohormone sorting signal-binding site on carboxypeptidase E, a regulated secretory pathway-sorting receptor. Molecular Endocrinology 13 527-536. (doi:10.1210/mend.13.4.0267)
171. Zhang CF, Dhanvantari S, Lou H & Loh YP 2003 Sorting of carboxypeptidase E to the regulated secretory pathway requires interaction of its transmembrane domain with lipid rafts. Biochemical Journal 369 453-460. (doi:10.1042/bj20020827)
172. Zhang X, Pan H, Peng B, Steiner DF, Pintar JE & Fricker LD 2010 Neuropeptidomic analysis establishes a major role for prohormone convertase-2 in neuropeptide biosynthesis. Journal of Neurochemistry 112 1168-1179. (doi:10.1111/j.1471-4159.2009.06530.x)
173. Zheng M, Streck RD, Scott RE, Seidah NG & Pintar JE 1994 The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. Journal of Neuroscience 14 4656-4673.
174. Zhou Y & Lindberg I 1993 Purification and characterization of the prohormone convertase PC1(PC3). Journal of Biological Chemistry 268 5615-5623.
175. Zhou A, Bloomquist BT & Mains RE 1993 The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthetic processing. Journal of Biological Chemistry 268 1763-1769.
176. Zhu X, Rouille Y, Lamango NS, Steiner DF & Lindberg I 1996 Internal cleavage of the inhibitory 7B2 carboxyl-terminal peptide by PC2: a potential mechanism for its inactivation. PNAS 93 4919-4924. (doi:10.1073/pnas.93.10.4919)
177. Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, et al. 2002 Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. PNAS 99 10293-10298. (doi:10.1073/ pnas.162352599)