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Review
. 2018 Oct 1;98(4):2381-2430.
doi: 10.1152/physrev.00024.2017.

POMC: The Physiological Power of Hormone Processing

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Free PMC article
Review

POMC: The Physiological Power of Hormone Processing

Erika Harno et al. Physiol Rev. .
Free PMC article

Abstract

Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissues and the impact of the simultaneous presence of their precursors or fragments. We also discuss the problems inherent in accurately measuring which of the precursors and their derived peptides are present in biological samples. We address how not being able to measure all the combinations of precursors and fragments quantitatively has affected our understanding of the pathophysiology associated with POMC processing. To understand how different ratios of peptides arise, we describe the role of the pro-hormone convertases (PCs) and their tissue specificities and consider the cellular processing pathways which enable regulated secretion of different peptides that play crucial roles in integrating a range of vital physiological functions. In the pituitary, correct processing of POMC peptides is essential to maintain the hypothalamic-pituitary-adrenal axis, and this processing can be disrupted in POMC-expressing tumors. In hypothalamic neurons expressing POMC, abnormalities in processing critically impact on the regulation of appetite, energy homeostasis, and body composition. More work is needed to understand whether expression of the POMC gene in a tissue equates to release of bioactive peptides. We suggest that this comprehensive view of POMC processing, with a focus on gaining a better understanding of the combination of peptides produced and their relative bioactivity, is a necessity for all involved in studying this fascinating physiological regulatory phenomenon.

Figures

FIGURE 1.
FIGURE 1.
Processing of human pro-opiomelanocortin (POMC) in different tissues. A: in the anterior lobe of the pituitary in humans. B: in the hypothalamus, skin, and pars intermedia of the pituitary. Pro-hormone convertase 1/3 (PC1/3) sequentially cleaves POMC → pro-ACTH → adrenocorticotropic hormone (ACTH). In hypothalamus, skin, and pars intermedia of the pituitary, ACTH is further cleaved by PC2 to produce ACTH (1–17) and corticotropin-like intermediate peptide (CLIP). Carboxypeptidase E (CPE) then cleaves basic amino acid residues from the COOH terminal, allowing amidation by peptidyl-glycine α-amidating monooxygenase (PAM) to form des-acetyl α-MSH (DA-α-MSH). N-acetyltransferase (N-AT) finally acetylates DA-α-MSH to produce α-MSH. PC2 cleaves β-lipotropic hormone (β-LPH) to β-endorphin (β-EP) and γ-LPH, which is further cleaved to β-MSH. The NH2-terminal peptide N-POMC has dibasic amino acids at the NH2 terminal of γ-MSH which are thought to be cleaved by PC2.
FIGURE 2.
FIGURE 2.
Species differences in the cleavage sites of pro-opiomelanocortin (POMC). The POMC gene has three exons with the translation start site in exon 2. Pro-hormone convertases (PC) cleave at dibasic sites comprising lysine (K) and arginine (R). These sites are generally well conserved, but occur at different amino acid numbers in the human, mouse/rat, and dog sequences. The absence of pairs of dibasic amino acids at the relevant sites in the rat/mouse POMC sequence predicts that γ-melanocyte stimulating hormone (MSH) and β-MSH will not be produced. ACTH, adrenocorticotropic hormone; CLIP, corticotropin-like intermediate peptide; β-LPH, β-lipotropic hormone; β-EP, β-endorphin.
FIGURE 3.
FIGURE 3.
Pro-opiomelanocortin (POMC) processing in neurons. POMC processing begins in the trans-Golgi network (TGN) which is based in the cell body in the arcuate nucleus (ARC). Very little is known about the sites of processing as the peptides move to the neuronal terminals in the paraventricular nucleus (PVN). There is some suggestion that N-acetyltransferase (N-AT) converts des-acetyl α-MSH (des-α-MSH) to α-MSH at the neuronal terminal such that α-MSH is released to activate melanocortin 4 receptor (MC4R) and decrease food intake (258, 312). POMC can also be processed in the nucleus tractus solitarius (NTS), where less is known about the processing of des-acetyl α-MSH and acetylated β-endorphin (β-EP) are the prominent peptides generated.
FIGURE 4.
FIGURE 4.
Alternative secretory pathways for precursors and pro-opiomelanocortin (POMC)-derived peptides. POMC is either stored in immature secretory granules (ISG) and released by constitutive secretion or processed and peptides stored in mature secretory granules (MSG) before release by regulated secretion. The anterior pituitary has prohormone convertase (PC) 1/3 and therefore processing is more limited than in the hypothalamus and skin, which have both PC1/3 and PC2 as well as other enzymes. This combination of additional enzymes gives rise to further posttranslational processing that results in the melanocyte stimulating hormone (MSH) peptides. TGN, trans-Golgi network; ACTH, adrenocorticotropic hormone; CLIP, corticotropin-like intermediate peptide; β-LPH, β-lipotropic hormone; β-EP, β-endorphin.
FIGURE 5.
FIGURE 5.
Pro-opiomelanocortin (POMC) processing generates numerous functional peptides. The primary roles of the different functional peptides cleaved from POMC are shown. ACTH, adrenocorticotropic hormone; β-LPH, β-lipotropic hormone; β-EP, β-endorphin; MSH, melanocyte stimulating hormone.
FIGURE 6.
FIGURE 6.
Regulatory processes for secretion of pro-opiomelanocortin (POMC) and its peptides. A: POMC moves from the trans-Golgi network (TGN) to immature secretory granules (ISG) and is secreted from cells by constitutive secretion. Pro-hormone convertase (PC) 1 cleaves POMC to produce adrenocorticotropic hormone (ACTH) which is stored in dense-core secretory granules (DCSGs) before secretion is stimulated. B: on stimulation, α-melanocyte stimulating hormone (MSH) and possibly ACTH is released from the cells in the hypothalamus/skin/pars intermedia of the anterior lobe of the pituitary. C: acute corticotropin releasing hormone (CRH) stimulation in the anterior pituitary causes the release of ACTH. POMC is also released but not subject to stimulation. D: long-term CRH stimulation upregulates the POMC gene and release of ACTH. E: glucocorticoids (Gcs) can inhibit ACTH secretion in an acute, nongenomic manner in the anterior pituitary. F: chronic exposure to glucocorticoids inhibits POMC transcription and ACTH release. [Adapted from Stevens and White (384), with permission from Springer Nature.]
FIGURE 7.
FIGURE 7.
Adrenocorticotropic hormone (ACTH) precursor secretion in ectopic ACTH syndrome. Pituitary tumors have excess production of ACTH, while ACTH precursors are released from ectopic (non-pituitary) tumors. The increased ACTH-related peptides lead to increased cortisol production. CRH, corticotropin releasing hormone.
FIGURE 8.
FIGURE 8.
Concentrations of adrenocorticotropic hormone (ACTH) precursors in different patient groups. The ranges relate to concentrations of ACTH precursors in blood samples from different groups of patients. The superscript numbers indicate the following references: 1, Ref. ; 2, Ref. ; 3, Ref. ; 4, Ref. ; 5, Ref. ; 6, Ref. .
FIGURE 9.
FIGURE 9.
Monoclonal antibody-based assays to pro-opiomelanocortin (POMC)-derived peptides. A: the monoclonal antibodies (MAbs) bind to specific epitopes on the peptides. A pair of antibodies is required for a two-site assay, which gives specificity. B: the adrenocorticotropic hormone (ACTH) precursor assay has one MAb specific for the ACTH region and one within the N-POMC region. C: the ACTH assay uses a pair of MAbs which recognize the NH2 and COOH regions of ACTH. They can recognize these epitopes in POMC but only bind ~2% of the precursors. HRP, horseradish peroxidase.

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