60 YEARS of POMC: POMC: the Consummate Peptide Hormone

56:4

a j l clark and p lowry 60 years of POMC 56:4 E1–E2 Editorial

60 years of POMC POMC: the consummate peptide hormone precursor

Correspondence Adrian J L Clark1 and Philip Lowry2 should be addressed to A J L Clark or P Lowry 1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, Email London, UK [email protected] or 2Emeritus Professor School of Biological Sciences, The University of Reading, Reading, UK [email protected]

Proopiomelanocortin (POMC) has been at the forefront peptidylglycine α-amidating monooxygenase enzymes of molecular endocrinology for the past 60 years, and the whose far wider role continues to be an active area of concepts derived from POMC research have led the way research and is reviewed by Dhivya Kumar and colleagues in understanding a wide range of endocrine systems. In (Kumar et al. 2016). The subsequent trafficking, sorting, this issue, we celebrate this enormous body of work with and storage of POMC products before secretion has also contributions from an outstanding faculty of contributors, contributed significantly to our knowledge of the broader many of whom have led these discoveries. The story aspects of this process and is reviewed by Peng Loh and begins approximately 60 years ago when Li and colleagues colleagues (Cawley et al. 2016). reported purifying and sequencing ACTH (Li et al. 1955, Cloning of the POMC gene confirmed the Dixon & Li 1956). They and others subsequently reported highly tissue-specific nature of its expression and purification of α- and β-MSH; however, it was with the simultaneously revealed the nature of its promoter. This discovery of β-LPH that the prohormone theory was enabled investigation into the factors controlling these advanced: that a single peptide precursor molecule could characteristics, and this fascinating work is discussed

Journal of Molecular Endocrinology contain several independent biologically active members. by Jacques Drouin, whose lab has led the way in this These discoveries, and his contributions to them, are area (Drouin 2016). Access to POMC sequences across reviewed by Phil Lowry (Lowry 2016). A key discovery a wide variety of species has permitted a fascinating was that of β-endorphin: Derek Smyth recalls his work understanding of the evolution of this and related genes and the events surrounding this (Smyth 2016). and is reviewed by Cerdá-Reverter and colleagues (Navarro Confirmation of the single-precursor concept et al. 2016). Equally fascinating is the evolution of the was provided by the cloning of the POMC gene by receptors for the melanocortin peptides derived from Nakanishi and coworkers; work reviewed by Adrian Clark POMC, and this topic is considered in depth by Robert (Clark 2016). Cloning of POMC additionally revealed Dores and colleagues (Dores et al. 2016). undiscovered N-terminal components of this precursor The biological actions of ACTH originally led to the whose potential biological function is reviewed by interest in purifying POMC, and those actions of ACTH Andrew Bicknell (Bicknell 2016). continue to fascinate. This complex subject is expertly Understanding the processing of these peptides reviewed by Nicole Gallo-Payet (Gallo-Payet 2016). More has provided fundamental models that are observed recently, the enormous role of POMC-derived MSH peptides extensively in peptide biology. Specifically, cleavage of in the regulation of appetite and food intake has been POMC into its active components requires the action of recognised, and we are fortunate to conclude this collection a novel series of enzymes, the prohormone convertases, with an outstanding article from Roger Cone, one of the reviewed by Michel Chretien and Majambu Mbikay major contributors in this area (Anderson et al. 2016). (Chretien & Mbikay 2016). Further processing of POMC These articles reveal several areas in which our products by C-terminal amidation revealed the class of understanding is deficient. Individual authors have

http://jme.endocrinology-journals.org © 2016 Society for Endocrinology This editorial accompanies a thematic review section on 60 Years of POMC. DOI: 10.1530/JME-16-0016 Published by Bioscientifica Ltd. The Guest Editors for this section were Adrian Clark and Philip Lowry. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 12:37:36PM via free access

10.1530/JME-16-0016 Journal of Molecular Endocrinology crinology andhasclearlynotyetgivenupallitssecrets. roleinthedevelopmentof molecularendo extraordinary to answertheseandotherquestions.POMChasplayedan inspire thenextgenerationofmolecularendocrinologists perceived asprejudicingtheimpartialityofthiseditorial. The authorsdeclarethatthereisnoconflictofinterestcould be Declaration ofinterest 4. 3. 2. 1. strike usasimportantarethefollowing: highlighted manyofthese;however, fourofthosethat DOI: 10.1530/JME-16-0016 http://jme.endocrinology-journals.org Editorial gland isstilllookingforafunctioninmammals. POMC peptidesitexpresses,thispartofthepituitary the RNAforcloningofPOMCandplethora Despite thebovineparsintermediabeingsource of that atleastγ-MSHformspartofitsnaturalagonist. oftheγ-MSHsequencewouldsuggest of conservation absence ofaMC3Rappearstocoincidewiththeloss would be of great interest. The fact that in teleosts the The identityofthenaturalPOMCagonistforMC3R the correctalignmentofdisulphidebridges. ones inwhichthesynthesishasbeendesignedtoensure workers inthisareatousethenaturalpeptidesor of vitalimportance,andwewouldencouragefuture molecular formofeachpeptidewouldappeartobe has stillnotbeenresolved.Here,inparticular, the which alltherelevantbiologicalactivityisexpressed and yetourfullunderstandingofthemechanismby credibility totheimportanceofthispartprecursor, the N-terminalregionofPOMChascertainlyadded duringevolutionofthestructure The conservation there unrecognisedfunctionsofthispeptide? MSH), whicheffectivelydestroysitsopiateactivity. Are intermedia, itisacetylatedatitsN-terminal(as with α- gland, giventhatwhenthereisafunctioningpars generated fromβ-LPHisamootpointinthepituitary the possibility of an opiate peptide revealed from this feature of its biochemistry. Even by virtueofitslipolyticactivity, littlemorehasbeen existence ofthePOMCprecursorandwasisolated Although lipotrophin was the first indication of the Ultimately, we hope that the articles in this issue will a

clark β-endorphin being and Printed inGreatBritain p

lowry Dores RM, Liang L, Davis P, &PetkoB201660yearsof Liang L, Thomas AL Dores RM, 1956Isolationandpropertiesofcorticotropinfrom &Li CH Dixon JS 201660yearsofPOMC:Theproopiomelanocortingene: Clark AJL 201660yearsofPOMC:Fromthe &Mbikay M Chretien M &Loh Li Z Cawley NX, 201660yearsofPOMC:N-terminalPOMCpeptidesand Bicknell AB Kumar D, Mains RE & Eipper E 201660yearsofPOMC:FromPOMC &Eipper E Mains RE Kumar D, 201660yearsofPOMC:Adrenalandextra-adrenal Gallo-Payet N 201660yearsofPOMC:TranscriptionalDrouin J andepigenetic Smyth D 201660yearsofPOMC:Lipotropinandbeta-endorphin:a Smyth D &Cerdá- Soengas JL Rotllant J, Puchol S, Soletto L, Navarro S, 201660yearsofPOMC:Purificationandbiological Lowry P 1955 &Dixon JS Harris JI Raacke ID, Cole RD, Geschwind II, Li CH, Anderson EJP, Çakir I, Carrington S, Cone RD, Ghamari- Cone RD, Anderson EJP, Carrington S, Çakir I, References the public,commercialornot-for-profit sector. This workdidnotreceiveanyspecificgrantfromfundingagencyin Funding Accepted 28 January 2016 Accepted 28January 2016 Received infinalform25January 60 yearsofPOMC Published byBioscientifica Ltd. (doi:10.1530/JME-16-0022) T119–T133. ofMolecularEndocrinology melanocortin peptides.Journal POMC: Melanocortinreceptors:evolutionofligandselectivityfor science.124.3228.934) glands.Science bovine pituitary T27–T37. discovery, ofMolecularEndocrinology56 deletionanddisease.Journal T49–T62. ofMolecularEndocrinology convertases (PCSK1toPCSK9).Journal toproopiomelanocortinandproprotein prohormone theory 0323) ofMolecularEndocrinology Journal trafficking andsecretionofproopiomelanocortin-derivedpeptides. (doi:10.1530/JME-15-0269) ofMolecularEndocrinology adrenal growth.Journal (doi:10.1530/JME-16-0014) and (doi:10.1530/JME-15-0257) ofMolecularEndocrinology functions ofACTH.Journal Endocrinology ofMolecular regulation ofPOMCgeneexpression.Journal perspective. 15-0288) ofMolecularEndocrinology56T113–T118.(doi:10.1530/JME- Journal perspective. 201660yearsofPOMC:Anevolutionary Reverter JM Molecular Endocrinology of characterisation ofmelanotrophinsandcorticotrophins.Journal (doi:10.1038/176687a0) Amino-acid sequenceofalpha-corticotropin.Nature 0266) ofMolecularEndocrinology Journal aMSH. of 201660years &Litt M Gillyard T, Gimenez LE Langroudi M, POMC: Regulationoffeedingandenergyhomeostasisby α MSH toPAM, molecularoxygen,copperandvitaminC. Journal ofMolecularEndocrinology Journal (doi:10.1530/JME-15-0268) (doi:10.1530/JME-15-0261) (doi:10.1530/JME-15-0292) Journal ofMolecularEndocrinology Journal 56 T99–T112.(doi:10.1530/JME-15-0289) YP 201660yearsofPOMC:Biosynthesis, 56 T1–T12.(doi:10.1530/JME-15-0260) Downloaded fromBioscientifica.com at09/28/202112:37:36PM 124 934.(doi:10.1126/ 56 T77–T97.(doi:10.1530/JME-15- 56 T63–T76.(doi:10.1530/JME-15- 56 T157–T174. 56 56 T13–T25. : 4 56 T39–T48. 176 687–689. 56 T135–T156. 56 E2 56 via freeaccess