Review articles

By Prof. Maria S Venetikou , Prof. Mohammad A Ghatei , Prof. Stephen R Bloom
Corresponding Author Prof. Maria S Venetikou
Technological Institutte of Athens, Aigaleo, Greece, 88, Agias Varvaras St - Greece 15231
Submitting Author Prof. Maria S Venetikou
Other Authors Prof. Mohammad A Ghatei
Department of Investigative Medicine, Imperial College, Hammersmith Hospital, London, UK, Department of Investigative Medicine, Imperial College, Hammersmith Hospital, London, UK - United Kingdom

Prof. Stephen R Bloom
Department of Investigative Medicine, Imperial College, Hammersmith Hospital, London, UK, Department of Investigative Medicine, Imperial College, Hammersmith Hospital, London, UK - United Kingdom


Convertases, Gene Structure, in Vitro and in Vivo Studies, Neuroendocrine Marker, Pituitary 7B2 (Isolation, Sequence), Pituitary Control

Venetikou MS, Ghatei MA, Bloom SR. 7B2, A Neuroendocrine Protein, Still Under Investigation for its Hormonal Role(s). WebmedCentral ENDOCRINOLOGY 2012;3(11):WMC003847
doi: 10.9754/journal.wmc.2012.003847

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submitted on: 22 Nov 2012 10:56:46 PM GMT
Published on: 23 Nov 2012 04:36:48 PM GMT


In this review article about the pituitary protein 7B2, we initially present the isolation and sequence analysis of the molecule and the development of a functional and sensitive radioimmunoassay.  We analyze the initial studies on the tissue distribution of 7B2 in various species including man.  We then discuss the in vitro and in vivo studies on the control of 7B2 release by various substances and its effect on different pituitary and other hormones.  Data from patients with major diseases and pituitary adenomas are also presented.  The subsequent efforts for studying 7B2 gene structure and cell role are emphasized.  The involvement of the protein as a possible neuroendocrine marker is discussed and relevant studies are presented.  Also the relationship of 7B2 with the proconvertase 2 (PC2) ant the possible cooperating mechanisms between the two molecules are emphasized. The way 7B2 regulates PC2 activation is also dealt with.  Possible emerging biological roles for the pituitary 7B2 are also presented, especially these coming from experiments with 7B2 null animals.  Since the protein is highly conserved among species a major biological role is presumed especially after the recent data from knock out (KO) animals.  Still a definite biological role for 7B2 in humans is not established yet.

Main Article

Isolation and sequence analysis

The pituitary gland, apart from its well characterized and extensively studied hormones, is also the source of many newly isolated biological molecules whose function remains either largely unknown or partially established.  A protein, isolated from porcine and human pituitary glands, named currently 7B2, consists of approximately 180 amino acid residues and has a molecular weight of 20,000 [1,2].  After its isolation by Hsi (1982), this protein was designated APPG (anterior pituitary pig).  It was purified by reverse phase liquid chromatography (RP- HPLC) from acid extracts of porcine anterior pituitary glands.  Amino – terminal sequence analysis showed the determination of the first 50 residues.  A computer data bank search using a mutation data matrix and comparison with 269,012 protein segments indicated then that this was a novel polypeptide sequence.  Only proinsulin, Rous sarcoma virus transforming protein (TVFV60) and secretin, bear suggestive sequence similarities (>20%) to this novel peptide.  Comparing the sequence of various proinsulins with that obtained for APPG, it was noted that starting from residue 26 of the B chain of proinsulins, duck proinsulin bore the greatest homology showing 15 out of 50 residue identities.  Comparing the sequence of the 50 APPG (7B2) residues with the segment 38 – 190 of Rous sarcoma virus transforming protein (TVFV60) and whole pig secretin (SEPG), it was seen that 7B2 was a novel sequence.  The structural homology to proinsulin, TVFV60 and SEPG was thought to be due to their possible common ancestral origin and perhaps to common functional properties.  No significant homology of APPG (7B2) to IGF I and IGF II was shown [1].  A year later the same group reported the isolation and purification of the first 17 and 81 residues of the human and porcine homologs of APPG [2].  Further data bank search was undertaken and out of 338,327 segments of proteins searched, representing a total of 2030 protein sequences, no significant match could be found except for the above mentioned molecules [2]. This substantiated that APPG (7B2) was indeed novel and should be classified as belonging to an entirely new superfamily.  It was then given the trial code name 7B2 with which it appeared thereafter in the literature.  Currently also the name secretogranin V (SGNE1) refers to the same molecule.

7B2 radioimmunoassay and tissue distribution

Initially a sensitive radioimmunoassay (RIA) for 7B2 immunoreactivity (7B2 – IR) was developed [3]. 

An initial immunocytochemical study [2] showed 7B2 to be present in the anterior and posterior lobes of the human, rat and mouse pituitary.  Specific staining was also found in the hypothalamic neurons (supraotic nucleus).  Other immunocytochemical studies reported that 7B2 was mainly localized in the gonadotrophs of the anterior pituitary [4].  The concentrations of 7B2 – IR in various rat tissues were also described [5]. The highest levels of 7B2 – IR were found in the anterior pituitary and in the intermediate lobe; moderately high concentrations were found in the thyroid gland, the hypothalamus and the adrenal medulla, whilst low concentrations were observed in the pancreas, ileum and colon. 7B2 – IR was not detected in the liver, the kidney, the lung, the spleen, the adrenal cortex and the testes.  Apart from the hypothalamus and the pituitary, 7B2 – IR is widely distributed in the human brain.  Highest concentrations are found in the substantia nigra and caudate nucleus [6]. 

Control of 7B2 secretion in vitro

In vitro, in anterior pituitary cell cultures, 7B2 secretion declined with time as also did GH and PRL secretion [7].  Since it has been reported that most of the pituitary 7B2 could be located in the gonadotrophs [4,8], and that LHRH could stimulate 7B2 secretion, normal pituitary dispersed cells were used and various concentrations of hypothalamic factors were tried in order to assess their involvement in 7B2 release.  LHRH at high concentrations caused a significant 7B2 release, but in all doses studied LH response was more significant.  CRH also at high doses caused 7B2 release but ACTH responses were much more sensitive to lower CRH doses.  GRH and TRH had no effect on 7B2 release from normal rat dispersed pituitary cells in vitro.  Various combinations of hypothalamic peptides were not shown to have an additional effect on 7B2 release [7].  Since a study reported that the pituitary protein 7B2 gene was coexpressed with pro - opiomelanocortin (POMC) gene and that it might be involved in directing membrane traffic at different steps in the secretory pathway in POMC producing pituitary cells [9], tumorous AtT – 20 cells were initially used for the investigation of 7B2 production and for the effect of various hypothalamic factors on ACTH and 7B2 release in time scheduled experiments in both static cultures and in perifusion columns.  CRH, AVP, VIP increased 7B2 secretion from the AtT – 20 cells significantly in 2 and 24 hour experiments and the combination of CRH and SRIH reduced both ACTH and 7B2 secretion [7].

Based on the initial observations of Marcinkiewicz and Steel and their colleagues [4,8], that 7B2 was colocalized in the pituitary gonadotrophs, its in vitro and in vivo response to LHRH, and the fact that it has been suggested in the past that human functionless pituitary tumours secrete in vitro gonadotrophins [10], all types of human pituitary adenomas obtained during transphenoidal surgery from various European Centres were initially studied   for 7B2 secretion in vitro.  These studies showed for the first time, the pituitary protein 7B2 to be secreted in vitro by functionless pituitary tumours in higher amounts than other adenoma types [11] and that somatotrophic tumours had also the ability to secrete 7B2 .                

Seidah and his colleagues suggested that 7B2 is synthesized in the hypothalamus and transported to the posterior pituitary in a way similar to that shown for AVP [2].  It was especially found in the neurons of the supraoptic nucleus, within the fibers of the median eminence and in the hypophysial stalk.  Granules of different forms and sizes have been reported in several areas of the hypothalamus , such as the paraventricular nucleus, both magnocellular and parvocellular, the lateral hypothalamic area and the area perifornicalis.  Colocalization of 7B2, AVP and dynorphin immunoreactivities within the supraoptic and paraventricular nuclei and the posterior pituitary was shown by Marcinkiewicz et al, [12].  Interestingly the whole area of 7B2 immunoreactive site was larger and extended to regions where AVP was absent (the intermediate and anterior pituitary lobes).  Using a perifusion system, the effects of cholinergic and osmotic stimulation (two known stimuli on AVP release) were compared on both 7B2 and AVP secretion from isolated rat hypothalami, in vitro [13].  Only depolarization induced by 56 mM KCl resulted in an increased 7B2 secretion.  Despite the close proximity of cells staining for 7B2 and AVP , there was no stimulation of 7B2 release by high (10-5 M) or low (10-8 M) acetylcholine concentrations or by osmotic stimuli.  Thus it was suggested that AVP and 7B2 respond differently to cholinergic and osmotic stimuli, in vitro [13].

In vivo studies of 7B2

The menstrual cycle, pregnancy  and the menopause

7B2 showed no tendency to increase during the ovulatory phase of the menstrual cycle [7].  It might be possible that the hormonal changes during the menstrual cycle are not sufficient enough to stimulate release of 7B2 – IR.  In contrast, significant changes in plasma 7B2 throughout pregnancy and one week after delivery were observed.  Levels were already increased by ten to twelve weeks and were highest during the four week period immediately prior to delivery.  Seven to ten days following delivery, 7B2 – IR was still significantly elevated compared to controls, but was significantly lower than that observed during the thirty six to forty week period [14]. The highest basal 7B2 changes in human pregnancy correspond to very dramatic hormonal changes that overshadow those that occur during the menstrual cycle.  When plasma 7B2 – IR was estimated in postmenopausal women a significant increase with age was observed.  This is in accordance with the studies published by Natori et al., [15] who showed an age – related elevation of plasma 7B2 – IR concentrations in 674 healthy subjects.  It should also be kept in mind that the tendency of 7B2 to increase in older women suggest also a close physiological relationship between 7B2 and the gonadotrophins, since it is well known that LH and FSH rise with age trough a negative feed – back mechanism [16].

Patients with pituitary adenomas

In the plasma of patients with GH, PRL and ACTH secreting adenomas 7B2 – IR was not significantly different from controls.  Some patients with functionless pituitary tumours showed the highest plasma 7B2 – IR.  The highest plasma 7B2 – IR noticed in female patients with functionless tumours, was observed where the LH secretion was more prominent [7], which is in accordance with the already mentioned in vitro observations that functionless tumours in culture continue to secrete higher amounts of 7B2 – IR when compared to other types of pituitary adenomas [11].  In particular only occasional prolactin and ACTH producing adenomas showed high 7B2 – IR, but some somatotrophinomas had higher plasma 7B2 levels, still significantly lower when compared with functionless tumours [7].

Patients with heart failure

Mild 7B2 increase was recorded in patients with heart failure and the most probable explanation to this so far was the reduction of the tissue perfusion due to congestive heart failure, since although patients with severe congestive heart failure had significantly higher plasma creatinine concentrations, which suggests renal impairment contributing to 7B2 rise, plasma 7B2 did not correlate with creatinine [7].

Patients with renal failure

7B2 was increased in patients with renal failure.  There was a further significant increase of 7B2 in patients with renal failure after haemodialysis.  7B2 values correlated significantly with plasma levels of creatinine [7].  These results are in accordance with a previously published report which showed increased 7B2 – IR in patients undergoing haemodialysis for treatment of their renal failure [17]. The 7B2 molecule does not seem to permeate through the dialysis membrane due to its molecular weight; therefore, the elevation of 7B2 – IR during hemodialysis is likely to be due to haemoconcentration [17].

Patients with liver disease

7B2 – IR was found to be increased in patients with liver disease [7]. In most of the patients with hepatocellular damage, 7B2 – IR ranged between one and a half to three – fold the normal range compared to control subjects.  It was obvious that in individual patients where liver disease was due to a metastatic tumour (Ca bronchus, metastatic carcinoid), 7B2 – IR was more than three to five fold increased compared to normal range.  This is in accordance with previous studies of Suzuki et al [18] who showed that 7B2 – IR is mostly encountered in neoplastic conditions, mainly endocrine or other tumours of the gastrointestinal tract.  Other peptides have been shown to be produced by primary liver tumours.  Neurotensin was shown to be produced by a fibrolamellar hepatoma [19]. In a multiple primary hepatic carcinoid tumour of the liver, neuron specific enolase (NSE) and chromogranin were demonstrated immunocytochemically in all cell tumour types [20]. It has also been suggested that 7B2 – IR is colocalized with several chromogranins in the secretory granules [21]. It is therefore possible that in patients whose disease is due to primary or secondary liver neoplasms, 7B2 – IR may be higher than in cirrhotics of other aetiologies, due to the overproduction of 7B2 by the tumour cells.           

7B2 protein and gene structures

Over the years, the complete sequence of 7B2 (see figures in Mbikay et al., Biochem. J. (2001) 357 (329–342) [37] was deduced from the sequence of cDNAs cloned in many species, organs and cell lines, including human anterior pituitary [22]22, rat pituitary [23], toad intermediate pituitary [24], rat insulinoma [25], pig adrenal medulla [25], fish hypothalamus [25], mollusk brain [27], nematode [28], and fruit fly [29].  The overall residue identity is very high (90 – 96%) among mammals, relatively high (67 – 83%) between frog or fish, and low (17 – 22%) between vertebrates and invertebrates.  The most conserved feature among all 7B2 sequences is Pro – Pro – Asn – Pro – Cys – Pro motif corresponding to residues 90 – 95 in human 7B2.  Among mammalians 7B2s, other conserved structural features include : clusters of basic residues (residues 139 – 140, 151 – 155 and 172 – 173), representing potential sites of processing by serine endoproteinases of the PC family [30, 31]; a serine phosporylation consensus site (Ser174) and a Glu – and Asp – rich acidic C – terminus (residues 180 – 186).  Interestingly, after the signal peptide, the only discontinuity among mammalian 7B2 sequences is the presence or the absence of an alanine residue following Thr99.  Southern – blot analysis of cDNA clones randomly retrieved from a cDNA library with isoform – specific 7B2 oligonucleotide probes showed that five out of the seven of these clones lacked the Ala100 codon [32].  Their coexistence in other endocrine tissues and in different species was suggested by heteroduplex analysis of DNA amplicons by reverse transcriptase – PCR of their RNA [32].  The alanine residue was absent in the cDNA – deduced porcine 7B2 sequence [25], but was present in the amino acid sequence of the 7B2 protein purified from pig pituitary extracts [33].  A variety of models can be proposed to explain the presence of Ala100 in the sequence of 7B2 protein purified from tissues and the prevalence of 7B2 transcripts without the Ala100 codon among cloned mRNAs.  On one hand, there is the possibility of preferential utilization of the Ala100 – encoding mRNA isoform for translation coupled or not with its selective degradation.  It is possible that the Ala100 protein may have a shorter half – life and may therefore be under – represented in tissue – extracted 7B2.

Differential translation has also been observed between anglefish prosomatostatin mRNA I and its isoform, II, which contains three octanucleotide repeats in its 5’ – untranslated region (UTR) [34].  Similarly, among the three insulin – like growth factor (IGF) mRNA isoforms of 6, 5 and 4.8 kb, differing by their leader sequence, the two shortest are preferentially utilized relative to the more abundant 6 kb isoform [36].  Although the structure of the 5’ – UTR may be determining the efficiency of initiation in these two examples, theoretical computation of the structure of codon100 and codon100 mRNA using the MFOLD program [36] produces distinctive stem – loop structures in the region encompassing this codon [37].  Such structural differences may influence the relative unwinding, translatability and stability of the two isoforms.  Preferential utilization of the codon100 – 7B2 mRNA may be associated with its selective degradation. Recruitement for translation is known to render some mRNAs susceptible to degradation by nucleases.  The degradation is initiated by endonucleases and completed by exonucleases.  Its extent may be partly determined by stabilizing or destabilizing RNA – binding proteins that recognize specific stem – loop structures in the mRNA [38].  Differential stability at the protein level is illustrated by the ΔΚ60human a1 globin mutation in which a single codon deletion leads to the production of protein that lacks Lys60 and is rapidly degraded [39].  Whether any of these models is applicable to 7B2 isoforms is still under investigation.  The variation is located within a structural loop generated by the single and functionally important disulphide bridge of the molecule.  In view of the conservation of these isoforms across mammalian species, it is conceivable that the single – residue difference may subtly influence the cellular functions of 7B2. 

The structure of 7B2 gene in rat and human is known [25, 40, 41].

The human gene (see figures in Mbikay et al., Biochem. J. (2001) 357 (329–342)) [37] is more than 30 kb long and is made of six exons.  Exon 1 specifies the 5’ – UTR of the mRNA, exon 2 specifies the signal peptide and residues 1 – 50 of pro7B2, exon 3 specifies residues 51 – 101, exon 4 specifies residues 102 – 138, exon 5 specifies residues 139 – 155, and exon 6 specifies residues 156 – 186.  The presence or absence of Ala100 is probably due to alternative utilization of two different 3’ splice sites that are three nucleotides apart at the end of the third intron [40].   Exons 4, 5 and 6 specify the two most important functional domains of 7B2.  The human 7B2 locus (SGNE1) maps on human chromosome 15q 42.  In mouse, its homologue (Sgne1) maps on the E3 – F3 region of chromosome 2 [40].   

7B2 as a neuroendocrine marker [37]

As already mentioned 7B2 is detectable in human plasma [17].  Its mean plasma level in healthy adults ranges from 40 – 140 pmol/l.  It is remarkably high (as high as 1 nmol/l) in early childhood, gradually decreases to adult levels by 20 years of age and slowly rises with aging.  As already mentioned it is elevated in pregnancy [14]    from the second to fourth trimester, but sharply declines soon after delivery, and returns to normal by 4 – 6 weeks post – partum.

The remarkable increase of plasma 7B2 in patients suffering from chronic kidney failure [7, 17]and liver cirrhosis [7[ suggests that these organs are involved in its clearance.  The variations of circulating 7B2 probably reflect the biosynthetic and secretory states of a variety of neuroendocrine cells.  However, the 7B2 reserve seems to be greater in some neuroendocrine cells than in others [4, 8], supporting the preferential storage with pituitary gonadotrophins.  A correlation between plasma 7B2 and plasma gonadotrophins was also reported in menopause and in patients suffering from Klinefelter’s syndrome, as well as in patients with various human chorionic gonadotrophin – secreting tumours.  7B2 was also shown to be actively secreted by functionless pituitary adenomas [11], which as already mentioned are often associated with gonadotrophin production.  High levels of circulating 7B2 have been detected in patients with other specific tumours of neuroendocrine origin.  Higher than normal plasma 7B2 levels have been observed in acromegalics with GH  - producing adenomas.  These levels were further increased when the patients were intravenously injected with GHRH  or TRH, but decreased following treatment with the somatostatin analogue SMS 201 – 995.  Likewise, patients with medullary carcinoma of the thyroid or pheochromocytoma showed elevated plasma 7B2 levels.  In contrast, these levels were within the normal range in patients affected by Cushing’s disease, prolactinoma or medullary carcinoma of the thyroid even after cell – specific exocytototic treatment [37].

Other biological fluids have been studied for their content of 7B2.  The normal concentration in cerebrospinal fluid is 10 – 100 fold greater than that found in the plasma (0.7 – 2 nmol/l) [6].  It decreases slightly with age, but is not significantly altered in cerebrovascular diseases.  It is also elevated in pleural effusion, with a mean concentration of 600 pmol/l, but does not vary significantly in benign or malignant pulmonary pathologies.  Immunological analysis of pathological tissues has revealed more extensive association of 7B2 with neuroendocrine tumours.  7B2 has been detected in nearly half of the pediatric peripheral neuroendocrine tumours of the bone, in the majority of benign and half of the malignant pancreatic tumours, mostly in insulin – producing ones. 7B2 was also present in a small fraction of medullary carcinomas of the thyroid, and among pituitary tumours, in gonadotropinomas and corticotropinomas, in benign and malignant phaeochromocytomas, in bronchial carcinoids and small – cell lung carcinomas [37].

The convertases : essential background to explain 7B2

Biologically active peptides and proteins are often generated by intracellular limited proteolysis of inactive precursors.  Currently, our understanding of this complex cellular mechanism has expanded.  It is now becoming clear that following removal of the signal peptide, precursor cleavage can occur either intracellularly, at the cell surface or within the extracellular milieu.  This evolutionary mechanism resulted in the elaboration of specific secretory enzymes and a tight regulation of their temporal and spatial activities.  These processing enzymes usually cleave proproteins at selected sites composed of single or paired basic amino acids.  The latter are found in precursors of most neural and peptide hormones, proteolytic enzymes, growth factors, and numerous type I membrane – bound proteins, including receptors, cell adhesion molecules, cell surface glycoproteins of pathogenic species such as viruses and bacteria and even cell signaling molecules and transcription factors.  Thus, the generation of biologically active peptides and proteins requires two major components, the polypeptide precursor substrate and the proteolytic enzyme(s) responsible for the conversion of the precursor into its final bioactive protein/peptide product(s).  For more than two decades there has been a debate about whether biologically active peptides/proteins are generated by a unique processing enzyme to each precursor or by enzymes that are relatively few in number with general and possibly redundant functions.  Recently, these questions have been answered [30].

The secretory enzymes responsible for this intracellular cleavage have also been molecularly and functionally characterized.  These convertases belong to an evolutionally conserved family of subtilisin – like (subtilases), calcium – dependent serine proteinases.  Based on the homology of the structure of their catalytic domains, they are considered to belong to the kexin subfamily of subtilases.  The seven known mammalian ‘Precursor Convertases’ (PCs) cleaving a single and/or pairs of basic residues have been named PC1 (also called PC3), PC2, furin (also called PACE), PACE4, PC4, PC5 (also called PC6) and PC7 (also called SPC7, LPC or PC8) [30].  These enzymes specialize in cleavage at basic residues (usually arginines).   

The identification of the proteinases responsible for such processing is needed, especially since they could play major roles in the regulation of cholesterol and fatty acid metabolism and in a number of neurodegenerative disorders such as Alzheimer disease [30]. This type of cellular processing has been implicated in the generation of bioactive peptides such as the neuroendocrine a- and γ- endorphin, the C terminal glycopeptide fragment 1 – 19 of pro – vasopressin, The N terminal pro – somatostatin – derived peptide antrin, platelet factor 4, the hormone relaxin, the metaloprotease ADAM – 10, site 1 cleavage of the sterol regulatory element binding proteins (SREBPs), as well as in the production of the Alzheimer’s amyloidogenic Ab peptides [30].  Processing of this type occurs either in the endoplasmic reticulum (ER)/early Golgi, late along with the secretory pathway, within secretory granules, at the cell surface, or in the endosomes.   It is suggested that the convertases evolved from a common ancestral gene through duplications, translocations, insertions or deletions.  High levels of expression of PC1 and PC2 mRNA were observed in neuropeptide rich regions such as the hypothalamus, hippocampus and cerebral cortex.  In general, PC1 mRNA distribution is more restricted, compared to PC2.  An impressing example is the thalamus, where almost all the thalamic nuclei express PC2 mRNA, but PC1 mRNA is found at high levels only in the anterior subdivisions.  The unique distribution patterns of PC1 and PC2 mRNAs and the observed differences in their relative ratios of expression at the cellular level suggests distinct roles in the activation of brain proproteins.  This variation in cellular mRNA levels may have significance for region – specific post – translational processing.  In other words, the same substrate proneuropeptide may well result in different biologically active end – products depending on the differential expression of PC1 and PC2 [30].  All PCs are first synthesized as zymogens (proPCs) which undergo autocatalytic processing of their prosegment within the ER, with the exception of proPC2, which is processed to PC2 within the trans Golgi network TGN/immature secretory granules compartment.  Of all the PCs, only PC2 requires a specific binding protein known as 7B2 (figure 3) and such binding improves the efficacy of productive zymogen activation of proPC2 to PC2 [30, 43]. It appears that PC2 is unique since is the only convertase undergoing pro – segment removal late along the secretory pathway (TGN/immature granules), has an Asp instead of the usual Asn at the site of the oxyanion hole, and requires the participation of a specific binding protein 7B2 for its effective zymogen activation. 

It is now clear that convertases exert a variety of functions from neuroendocrine to endocrine and immune response regulation.  The PCs research may find medical applications in the future, especially in the therapeutics of a number of pathologies including atherosclerosis, neurological and endocrine dysfunctions, cardiovascular and proliferative diseases as well as opportunistic pathogenic infections.

PC2 and 7B2 (see figures in Mbikay et al., Biochem. J. (2001) 357 (329–342)) [37]

It was a breakthrough in the study of 7B2 when Braks and Martens [43], led by structural similarities between the first 90 – amino acid sequence of 7B2 and a segment of human, wheat and Escherichia coli chaperonins, gathered experimental evidence showing that a recombinant 7B2, added to metabolically radiolabelled Xenopus pituitary extracts and immunoprecipitated, can retrieve the various forms of PC2 from the extracts.. They also showed by pulse – chase studies that proPC2 is bound in the early compartments of the secretory pathway and dissociates from it in later ones.  They proposed that 7B2 serves as an intracellular proPC2 chaperone and prevents the premature activation of the zymogen during its transit in the regulatory pathway.  The dynamic interaction between these two neuroendocrine molecules was further characterized in numerous other studies[44, 45, 46].  The results globally support the model of 7B2 – PC2 interaction.  Pro7B2 attaches to proPC2 in the ER.  This attachment is facilitated by the relatively alkaline conditions of this compartment.  The inactive complex is transported to the TGN where pro7B2 is cleaved into an N – terminal protein and a C – terminal peptide.  ProPC2 then gets autocatallitically cleaved after the prodomain and the complex is transported into secretory granules.  In the acidic environment of these organelles, the prodomain and the 7B2 fragments dissociate from the enzyme, which then becomes fully active.  Depending on experimental cell systems and conditions, variations from this model have also been observed.  Pulse – chase studies of newly synthesized proteins have shown that pro7B2 is transported out of the ER faster than proPC2, suggesting that the former needs not interact with the latter for its trafficking in the secretory pathway.  Newly made proPC2, on the other hand, exits the ER much more slowly and must acquire a proper conformation to do so.  This conformational change is also required for the zymogen to bind passing pro7B2.  Through the conformation the zymogen is presumably rendered more stable, allowing a faster migration from the ER to the Golgi.  7B2 and PC2 proteins are both packaged into the secretory granules.  It is unclear whether proPC2 needs to be associated with 7B2 polypeptides to be sorted into these organelles.  Although not yet established, it may be a component of PC2 aggregates that are sorted into the secretory granules.  It has been shown to aggregate on its own in a calcium – and pH – dependent manner.  In part because of this property, it has been grouped with chromogranins and secretogranins into the so called granin family of proteins, one of whose presumed functions is to facilitate the sorting of neuroendocrine proteins into secretory granules.   

7B2 regulates PC2 activation

The interaction of proPC2 with 7B2 may be both facilitative and regulatory with regard to the maturation and activation of the enzyme.  Apparently, not all 7B2 molecular forms can promote this maturation.  The precursor form, through its carboxy region, may block, or at least interfere with, this maturation.  Its prior processing might be required to allow proPC2 cleavage.  Thus, when supplemented to a cell – free translation lysate derived from Xenopus intermediate pituitary cells, mature 7B2, but not its unprocessed precursor, could stimulate PC2 – mediated processing of POMC [47].

C – terminal domain of 7B2 (7B2CT) peptide, a specific inhibitor of PC2

The 7B2CT peptide that follows the quintuplet has been shown to strongly inhibit PC2 activity in vitro at nanomolar levels [48, 49].  The Lys172 –Lys173 pair is important for the binding and the inhibitory properties of the peptide [43, 46].  These properties are conserved across species as they have been observed with Lymnae and Caenorhabditis elegans 7B2 [27, 28].  However, there is no clear – cut experimental evidence showing that 7B2CT has any PC2 – inhibitory activity in vivo.  Clearly, the in vitro conditions that have permitted the identification of the inhibitory activity of the 7B2CT peptide can hardly be construed to replicate those existing in the secretory compartments of cells.  The 7B2CT peptide, within the pro7B2 context, may indeed interfere with proPC2 conversion to PC2, but only in pre – TGN compartments.  Once it is processed by furin in the TGN, its products remain bound to the zymogen but can no longer prevent the latter from being matured, either autocatalytically, or by related PCs, such as furin and PACE4.  Once matured, the enzyme may become susceptible to inhibition by both its own propeptide and by 7B2CT peptide [37].

Evidence for other roles of 7B2

Helping in the trafficking of PC2 and controlling the temporal activation of PC2 may not be the only cellular function of 7B2.  Indeed, in situ hybridization studies on the rat brain have shown that whereas all the cells containing PC2 transcripts also contain 7B2 transcripts, there are many cells containing the latter without containing the former [50].  In a study of Xenopus laevis ontogeny, 7B2 mRNA was found in unfertilized eggs, as well as in the earliest developmental stages, whereas PC2 mRNA became detectable only after embryonic neurogenesis [51].

Wolfram syndrome (WS) which was first described in 1938  in 4 siblings is characterized by optic atrophy, insulin dependent diabetes mellitus, vasopressin (VP) – sensitive diabetes insipidus, and neurosecretory hearing loss.  A study by Gabreels et al., [52], reported a disturbance in VP precursor processing in the supraoptic and paraventricular nuclei of WS patients.  In these patients with diabetes insipidus, they could hardly detect any cellular immunoreactivity for processed VP in the supraoptic and paraventricular nuclei.  On the other hand, in the paraventricular nucleus a considerable number of cells immunoreactive for the VP precursor were present.  In addition the proprotein PC2 and the molecular chaperone 7B2 were absent.  As expression of PC2 and 7B2 was detected in the nearby nucleus basalis of Meynert of one WS patient and in the anterior pituitary lobe of the other WS patient, the absence of the two proteins in the paraventricular nucleus was not due to mutations in their genes.  It was then suggested that in WS patients with diabetes insipidus, not only does VP neuron loss occur in the supraoptic nucleus, but there is also a defect in VP precursor processing.

The likelihood of other cellular roles for 7B2 has been made most evident by the .remarkable phenotype of the 7B2 knockout mice generated by Westphal et al; [53]. Like in their PC2 – knockout counterparts, PC2 activity is lacking in these mice and processing of pancreatic islet prohormones is severely impaired.  However, unlike PC2 null mutants, which are viable, 7B2 null mutants die within weeks after birth from severe Cushing’s disease due to the excessive secretion of corticotrophin by the intermediate lobe of the pituitary.  It is unclear which of the various 7B2 peptides are involved in secretion regulation or whether they act in intracrine, autocrine or paracrine fashion.  One of them, the C – terminal 7B2 174-186 peptide, has been shown to induce membrane depolarization of vasopressin and oxytocin of supraoptic nucleus neurons when applied to hypothalamic explants [54].

More should be said about the interesting observations of Westphal et al., [53],who in their effort to elucidate the mechanism of interaction of 7B2 and PC2 and to provide in vivo evidence of the link between 7B2 and PC2 activity, they generated 7B2 null mice using a novel transposon – based technique [55]. These mice lack the PC2 activity, and have multiple metabolic derangements, similar but not identical to the PC2 null mice [56].  Interestingly, in contrast to PC2 null mice , 7B2 null mice develop and die of Cushing’s disease, with multiple sequelae of hypercorticosteronism, indicating a novel role for 7B2 in the normal control of peptides from the pituitary.  7B2 null mice are deficient in proPC2 protein maturation and devoid of PC2 activity, confirming earlier studies about PC2 activity’s total dependence upon 7B2 expression, and the physiological requirement of 7B2 for PC2 activation.  The generation of mature glucagons is essentially eliminated in 7B2 null islets and only small amounts of intermediate cleavage products are generated, in contrast to the rapid and complete conversion to glucagons in wild – type islets.  In the brain, the production of mature enkephalins is known to be dependent upon PC2 activity.  The levels of mature enkephalins are dramatically reduced in PC2 null brains.  In 7B2 null brains the levels of two mature enkephalins are also dramatically reduced, and these data supported that the lack of PC2 activity seen in 7B2 null mice leads to significantly reduced tissue levels of mature glucagons, insulin and enkephalins.  These 7B2 mutant mice manifest severe metabolic abnormalities.  At 4 – 5 weeks of age, 7B2 null mice are severely runted, hypoglycaemic and have elevated circulating insulin – like material.  Clear clinical signs of abnormality are apparent in these animals even at 4 days of age.  7B2 null mice are pale and ecchymotic and many suffer from significant bruising into the abdomen, leading to their pale appearance.  Only 11% survive to weaning.  Despite initial runting, those null mice that survive to weaning show abnormal fat deposition, especially on the back and around the neck.  Given the abnormal pattern of the fat deposition observed in 7B2 null animals, a problem with the pituitary/adrenal axis was suspected.  Total pituitary ACTH was found increased 10 to 20 – fold in null 7B2 mutants compared with wild – type mice with none of the ACTH cleavage product CLIP (corticotrophin – like intermediate peptide).  Biosynthetic studies of POMC processing in whole pituitaries showed markedly elevated production of intact ACTH and minimal conversion of this peptide to a – MSH, a processing event normally mediated by PC2 in the intermediate lobe.  Immunohistochemical studies showed marked reduction in anterior staining for ACTH in 7B2 nulls.  Consistent with the increased pituitary levels of ACTH, circulating levels of ACTH in plasma obtained from 7B2 null animals was greately elevated over controls.  Serum corticosterone was elevated approximately 4 – fold in 7B2 mutant mice. 7B2 null mice exhibited cortical hyperplasia.  All these findings taken together supported a diagnosis of Cushing’s syndrome in these animals.  7B2 null mice exhibited also marked thinning of the skin and dermal atrophy with hyperkeratosis.  7B2 nulls showed a typical dorsal cervical ‘buffalo hump’ of fat, classical of Cushing’s visible at 7 weeks.  The 7B2 nulls exhibit essential differences from both wild – type and PC2 nulls especially in the control of the intermediate lobe pituitary secretion.  Hypersecretion from the intermediate lobe constitutes the most likely mechanism for the elevated plasma ACTH secretion observed in the 7B2 null animal.  Animal models for Cushing’s disease such as the D2 receptor null mouse and the CRH transgenic mouse, both develop a less severe Cushing phenotype, with normal life spans !  It is of interest that adrenalectomization of 7B2 knockout mice avoided the lethal Cushing’s syndrome but these animals developed severe obesity [57].  Background effects must be critical because they increase the phenotype differences between types of 7B2 and PC2 nulls and play a life – or  - death role in the ACTH hypersecretion syndrome present in a type called the 129 7B2 null [58].

It is also of interest that the tumorous cell line (ATt20 cells) which in vitro secrete ACTH, also secrete increased quantities of 7B2 in vitro [59].

Since 7B2 was shown to be a regulator/activator of the prohormone convertase 2 (preproPC2) which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro – opiomelanocortin (POMC), a recent study [60] from a French group which in the past described a suggestive genetic linkage peak with childhood obesity on chr15q12 – q14, where the 7B2 encoding gene, SGNE1 (Secretory Granule Neuroendocrine protein1) is located, undertook a study to analyse associations of SGNE1 genetic variation with obesity and metabolism related quantitative traits.  They did not find associations between SGNE1single nucleotide polymorphisms (SNPs) and childhood or adult obesity.  SGNE1 genetic variation does not seem to contribute to severe obesity in both children and adults [60].

Currently the history on 7B2 research dates at least twenty years and there still remain many unanswered questions.  It is possible that 7B2 which is more widely distributed than PC2 and has for long been used as a neuroendocrine marker, may have many physiological roles other than its interaction with PC2.  Because 7B2 especially in the brain shows a pan – neuronal mRNA expression and PC2 shows a more restricted,  sparing some regions expression, it seems possible that 7B2 has an additional function at least in non PC2 expressing cells [50].

Another recent study [61] identifies the SGNE1 as a novel epigenetically silenced gene in meduloblastomas.  Its frequent inactivation, as well as its inhibitory effect on tumour cell proliferation, strongly argues for a significant role in medulloblastoma development [61].

The wordwide research on 7B2 physiological function and its involvement in disease still continues and appears that intriguing data may follow such extensive studies.


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