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Chromogranin A: Its Role in Endocrine Function and As an Endocrine and Neuroendocrine Tumor Marker*

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Chromogranin A: Its Role in Endocrine Function and As an Endocrine and Neuroendocrine Tumor Marker* 0163-769X/91/1202-0181$03.00/0 Endocrine Reviews Vol. 12, No. 2 Copyright <$ 1991 by The Endocrine Society Printed in U.S.A. Chromogranin A: Its Role in Endocrine Function and as an Endocrine and Neuroendocrine Tumor Marker* L. J. DEFTOS Department of Medicine, University of California San Diego and the San Diego Veterans Administration Medical Center, La Jolla, California 92161 Downloaded from https://academic.oup.com/edrv/article/12/2/181/2548640 by guest on 27 September 2021 I. Introduction low isoelectric points. The abundance of acidic amino acid residues results in an anomalous electrophoretic HROMOGRANIN A (CgA) is a 49 kilodalton pro- mobility for CgA (3). There is considerable structural tein that is produced exclusively by endocrine and C homology among the CgAs, especially at their amino- neuroendocrine cells (1-3). CgA was originally discovered and carboxy termini (Fig. 1). Each species has a hydro- in the chromaffin granules of the adrenal medulla, hence phobic leader sequence, a 17,38 disulfide bridge, and an its name (1-3). The adrenal gland is the main organ internal homology at residues 250-301 to pancreastatin source of CgA, where it is the major soluble protein of (22). Nine serine sites are conserved in CgA, some of catecholamine secretory granules (2, 4). Furthermore, CgA is found in a variety of endocrine and neuroendo- which are potential sites for cAMP-dependent phos- crine cells and tissues that have electron-dense core phorylation and consequent modification of biological secretory granules and is absent in such tissues that do activity; however, the importance of phosphorylation for not; however, CgA is not present in exocrine cells (1-5). CgA has not been established. An RGD sequence is CgA has also been demonstrated in human neurons and present at residues 43-45 in the bovine, human, and in the central nervous system (1, 5, 6) and is present in porcine species but is not conserved at the same site in submammalian species (7, 8). CgA is costored and cose- rat CgA, although an RGD moiety is present at residues creted with the resident hormones of these secretory 399-401 in this species (Fig. 1). Thus, it is unlikely that granules, such as catecholamines and calcitonin (CT) (9, the RGD moiety has an important membrane binding 10). In these other endocrine sites, as in the adrenal function for CgA, especially since it is primarily a cyto- medulla and thyroid C cells, CgA is in the same secretory solic protein. Sites for glycosylation are present in essen- granule as the associated hormones (9-11). The gene for tially all CgAs, and O-glycosylation produces a protein CgA has been localized to chromosome 14 (12). Although that contains approximately 3-5% carbohydrate (3). All the function of CgA is not known, it can serve as a tissue of the CgAs contain many dibasic residues, potential and serum marker for a variety of endocrine cells and cleavage and peptide processing sites, and seven of these tumors (9-15). Thus, the identification of CgA by im- dibasic sites are conserved in all CgA species (Figs. 1 and munohistology and the measurement of CgA by immu- 2). Processing at these sites can lead to the release of noassay represent new diagnostic tools for the endocri- peptides with unique biological effects, as discussed be- nologist (9, 16). low. Several oligoglutamic regions are present in the CgAs, with conservation at the 220-224 site. Three pu- tative binding domains for calcium have been postulated II. Biochemistry for CgA based on respective homologies to s-100 /3- The amino acid sequence of CgA has been deduced protein, intestinal calcium-binding protein, and rat on- from the nucleotide sequence of the protein in several comodulin (23-27). Although CgA does bind calcium in species, namely human, bovine, porcine, and rat (17-21); vitro, the binding affinity is low compared to other au- CgA is found in fish as well as mammalian endocrine thentic calcium-binding proteins, so the physiological glands (7, 13). All species of CgA are hydrophilic with relevance of this observation is unclear (3,25,26). Never- theless, the presence of multiple potential calcium-bind- Address requests for reprints to: Dr Leonard J. Deftos, Department ing sites in CgA, even though of moderate affinity, may of Medicine, San Diego Veterans Administration Medical Center, 3350 confer significant binding activity to the entire molecule La Jolla Village Drive, San Deigo, California 92161. (3, 27). * Supported by the National Institutes of Health, the National Cancer Institute, and the Department of Veterans Affairs. CgA has been likened to several other high molecular 181 182 DEFTOS Vol. 12, No. 2 CHROMOGRANIN A -18 +1 hCgA MRSAAVLALLLCAGQVTALPVNSPMNKGDTEVMKCIVEVISDTLSKPSPMPVSQECFETLRGDERILSILRHQNLLKELQDLALQGAKERA HQQKKHSGFEDELSEVLENQSSQAELK bCgA -T SY KPND—P- pCgA I S Q-SY ND rCgA —S-A F- T—-K----VL S P--L—Q—-V QQQQQQQQQQQQQQQQ--QQ F—-PA-KIIG 101 hCgA EAVEEPSSKDVMEKREDSKEAEKS.. GEATDGARPQALPEPMQESKAEGNNQAPGEEEEEEEEATNTHPPASLPSQKYPGPQAEGDSE.GLS. QGLVDREKGLS 200 bCgA -VT--V AA—0 V D-DS--D S-GLGPGP-V-ED APS-A--L P KE— .-P-.--PAS pCgA _GT--A AA—G N... .-A—K—SL--P.XXXEA--.-T--. K-R--A H-..--. P- rCgA D-AS-AP—TV DKGQQDAFEGT-E-P FP--K—SMM--S-S-- -DT-N--QS-T EHGI--TT-G--R—A-QQ-RKA-QEE 201 hCgA AEPGWQAKREEEEEEEEEAEAGEEAVPEEE..GPTVVLNPHPSLGYKEI.RK..GESRSEALAVDGAGKPGAEEAQDPEGKGEQEHSQQKEEEEE.MAVVPQ 300 bCgA --Q-R-TE KW R-K .SP-AAFK-P—-N--TQ-AAP-WPE H KP WA--R-.-—. .--RA-- pCgA —-P-A A-. .G-RSE--DS M--... —. .QAP-M T AR .— -. .T-G— rCgA K-EEEEE-E K-I G-K-..V—-.SSS-FYS—K--KDDD-QS--Q..--N..--T--S--VPS L E-DG-A--GP- 301 hCgA GLFRGGK SGELEQE.EE.RLSKEWEDSKRWSKMDQLAKELTAEKRLEG.. .QEEEED... .NRDSSMKLSrRARAYGFRGPGPQLRRGWRPSSREDSLEAGLPL 400 bCgA V--H— —PK-.. .-.Q A .E—-E... .DP-R-R G L N-Q—V Downloaded from https://academic.oup.com/edrv/article/12/2/181/2548640 by guest on 27 September 2021 pCgA R-PA-.-E—E—NA R Q-...E EEEEEDP-R P L V rCgA —P—GQELERKQQ-E-E-.--R--.R R - — D 401 hCgA QVRGYPEEKKEEEEGSANRRPEDQELESLSAIEAELEKVAHQLQALRRG 439 bCgA EE pCgA ..X—L P—S rCgA ..--DF A FIG. 1. Amino acid sequence of human chromogranin A (hCgA) compared to the bovine (bCgA), porcine (pCgA), and rat (rCgA) forms. Alignments are made to demonstrate homologies. The pancreastatin region for hCgA is residues 250-231. Potential dibasic cleavage sites for hCgA are summarized in Fig. 2. [Adapted from Refs. 17-21.] (77) (114) (200) (248) (322)(335)(373)(400)(409)(437) V100V 200V V 300 VV V VV V CgA 1-L J-439 PEPTIDE rzi EFFECT CT 0 + CGRP + 0 0 PTH - PTHrP Insulin — FIG. 2. The effect of CgA-derived peptides on the secretion of its coresident peptide hormones. The linear sequence of human CgA is represented along with the location (V) of dibasic sites of potential processing. The effect of the CgA-derived peptides CgA 1-40, CgA 250-301 (pancreastatin sequence), and CgA 403-428 on the secretion of hormones is summarized: +, stimulation of secretion; -, inhibition of secretion; 0, no effect; absence of a symbol indicates that testing was not done. In addition to these data, an inhibition of catecholamine secretion is produced by an unidentified cleavage product of CgA (32), and preliminary work has reported the inhibition of ACTH and somatostatin by CgA-derived peptides (36). [Data from Refs. 32-36.] weight proteins found in neuroendocrine and endocrine Despite these structural similarities among CgA, CgB, tissues and variably named as CgB (Secretogranin I), and CgC, one can only speculate about any functional CgC (Secretogranin II), and 0-granin (3, 28). There is similarities among this group of proteins based on cur- considerable homology between CgA and CgB at their rent evidence (3, 27-29). Many of the structural homol- respective amino-terminal disulfide-bonded loops and at ogies are either weak or not conserved among the various their carboxy termini, as there is between /3-granin and species of the CgAs that have been studied. Although the amino terminus of CgA. CgC also has significant CgA, CgB, and CgC have some common tissue and cell- homologies to the carboxy-terminal sequences of CgA ular locations, CgA has the widest tissue distribution and and CgB, but CgC lacks cysteine residues (28). The significance of these sequence homologies is generally is present in some cells that do not express CgB and CgC unknown, although it has been postulated that, like (3, 28). Furthermore, these other chromogranins acquire pancreastatin, discussed later, /?-granin is a cleavage posttranslational modifications, such as tyrosine sulfa- product of CgA (3, 29). In fact, CgA, CgB, and CgC each tion, that are not present in CgA (3). Nevertheless, there contain multiple dibasic residues that are potential sites are enough common features among these molecules to for proteolytic processing to smaller peptides (3, 17-21). postulate that they are members of a family (3, 27). This May, 1991 CHROMOGRANIN A 183 view is further supported by the presence of these pro- (3, 30). Support for this view regarding the functional teins in the same secretory vesicles in some tissues (3). implications of this property of CgA has come from The most consistent and striking homology among the several observations. CgAs is the presence of a large number of dibasic sites In the bovine adrenal, proteolytic cleavage of native for potential cleavage and processing, ranging up to 10 CgA has been reported to inhibit the secretion of cate- in the human species (17-21). The number of dibasic cholamines, whereas the native molecule itself has no sites far exceeds that observed for any other family of such effect (32).
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