PGRMC2, a yet uncharacterized protein with potential as tumor suppressor, migration inhibitor, and regulator of cytochrome P450 enzyme activity
Highlights
► PGRMC2 is highly homologous to PGRMC1. ► In contrast to PGRMC1, PGRMC2 is rather a tumor suppressor, than a promoter. ► PGRMC2 inhibits cancer cell migration. ► PGRMC2 might be involved in gynaecologic diseases (endometriosis and preterm labour). ► PGRCMC2 binds cytochrome P450 proteins and seems to influence their activity.
Introduction
In the nineties, Gerdes et al. cloned two human membrane proteins and identified them as putative progesterone receptors HPR6.6 (PGRMC1) and Dg6 (PGRMC2)[1].
PGRMC1 was characterized in several cell types and has been shown to be overexpressed in several cancer cell lines and tissues [2]. The protein seems to play a role in chemotherapy resistance and was shown to promote the antiapoptotic effect of progesterone [3], [4], [5]. Further it was shown to bind several cytochrome P450 enzymes [6], [7].
PGRMC2 is highly homologous to PGRMC1. Sequence alignment and phylogenetic analysis indicate that PGRMC1 and 2 may have diverged from a common gene. It is therefore tempting to speculate that the proteins have similar functions. Both proteins consist of an N-terminal extracellular domain, followed by a transmembrane domain and a larger cytoplasmic domain. The cytoplasmic domain contains a cytochrome b5 similar heme-binding domain [8]. This cytochrome b5 similar heme binding domain is highly conserved, including the region for ERK binding and Lck/Abl tyrosine kinase binding, and the putative SH2 target sequence [9]. Further a C-terminal putative SH2 target sequence is also present in both proteins [9]. Sequences of the both proteins are quite different at the N-terminal end and the transmembrane domain pointing to the possibility of distinct interacting proteins. PGRMC2 is located on chromosome 4 while PGRMC1 is located on the X chromosome.
While PGRMC1 has been examined in several cells, tissues and contexts, PGRMC2 was not thoroughly characterized until now. Those limited but interesting facts for PGRMC2 will be summarised in the following.
Section snippets
Localisation of PGRMC2
In SKOV-3 ovarian cancer cells PGRMC2 was shown to be mainly localised in the endoplasmatic reticulum (ER) [10]. Further a localisation in the cytoplasm and in the nucleus was detected, but most of the protein was localised at the ER. For PGRMC1 the localisation was the same [10].
In the endometrium of macaques PGRMC2 was localised in the cytoplasm of the epithelial cells of both functionalis and basalis glands. In macaques with endometriosis the localisation of PGRMC2 changed to the nuclear
Expression of PGRMC2
PGRMC2 is expressed in several tissues, with especially high expression in the placenta [1]. Expression of PGRMC2 was found to be influenced by several different conditions in different cell types. For example, estrogen receptor α has no effect on the expression of PGRMC1 but correlates with the expression of PGRMC2 in breast cancer tissue. Further PGRMC2 is increased in stage III cancer tissue compared to stage II, while in the same study no effect is visible for PGRMC1 in breast cancer tissue
Regulation of PGRMC2
Virtually nothing is known about the regulation of PGRMC2, but a recent study demonstrates that PGRMC2 contains an ubiquitylation site [16]. The most studied function of ubiquitylation is the role of substrate linked ubiquitin as a proteasomal degradation signal for target proteins in the ubiquitin proteasome system (UPS). Post translational modification of proteins by ubiquitin is a reversible regulatory mechanism, which plays an important role in several cellular processes like DNA damage
PGRMC2 in other organisms
The porcine PGRMC2 was cloned in 2010 and molecular characterisation was performed [23]. In this study, two transcripts were found. The sequence has 96% similarity to the human PGRMC2. The authors showed that the genomic organization of PGRMC2 from several mammals is similar. All consist of two introns and three exons. The exon/intron boundaries are absolutely conserved among all tested mammals [23]. This indicates that PGRMC2 is well conserved in evolution.
PGRMC2 in pig was expressed in all
PGRMC2 in cancer
PGRMC1 seems to play a role in tumor promotion and chemotherapy resistance of cancer cells [3], [4], [5]. The role of PGRMC2 in cancer has not yet been studied in detail, but there are hints that PGRMC2 plays a role in tumor suppression and not, as PGRMC1, in tumor promotion.
For example, in nodal metastasis of endocervical adenocarcinomas in the uterus a high rate of loss of PGRMC2 was detected suggesting that PGRMC2 might act as a tumor suppressor in metastasis of endocervical adenocarcinoma
PGRMC2 in preterm/term labour
In the choriodecidua, PGRMC2 is upregulated in term and preterm labour and seems to be regulated by the labour specific hormonal environment [29], but the function of this protein in pregnancy and labour has not been analysed yet. For PGRMC1 it was already shown that PGRMC1 is upregulated in pregnancy and downregulated in term and preterm labour [30]. Therefore PGRMC1 may contribute to the onset of labour by withdrawal of the PGRMC1 receptors. It was further speculated that PGRMC1 is involved
Potential involvements of PGRMC2 in further diseases
A slight upregulation of PGRMC2 in patients with diminished ovarian reserve was detected [32], but this result needs confirmation. For PGRMC1 it was shown that women with premature ovarian failure often show mutant or reduced levels of PGRMC1 [11], [33]. Analogous data for PGRMC2 are scarce, and further studies need to clarify the involvement of both receptors in these diseases.
Alterations in PGRMC1 expression and localisation were also found in the endometrium of macaques with endometriosis
Binding partners of PGRMC2
PGRMC1 has been shown to form big protein complexes. Binding partners for PGRMC1 are Insig (insulin induced gene), SCAP (SREBP cleavage activation protein), PAIR-BP (plasminogen activator inhibitor RNA binding protein-1) (Fig. 1) and an unknown steroid binding protein [34]. Whether these proteins are also binding partners of PGRMC2 or not, remains to be elucidated.
Further it has been shown that PGRMC1 binds cytochrome P450 (CYP) proteins like CYP51, CYP21A2, CYP21, CYP7A1 and CYP3A4 (Fig. 1)
Outlook
PGRMC2 has not been thoroughly characterized until now, but it shares several characteristics with PGRMC1, like overall sequence homology, localisation, and binding of CYPs. Nevertheless PGRMC2 has interesting characteristics which clearly differ from those of PGRMC1. In contrast to PGRMC1, PGRMC2 negatively influences migration velocity in ovarian cancer cells and a high rate of loss of PGRMC2 was detected in nodal metastasis in endocervical adenocarcinomas. Therefore PGRMC2 might play an
Conflict of interest statement
AW has nothing to declare. MW was employed by AstraZeneca R&D, Mölndal, as director of discovery medicine (= translational medicine) from 2004–2006, while on sabbatical leave from his professorship at the University of Heidelberg. After return to this position in January 2007, he received lecturing and consulting fees from Sanofi-Aventis, Novartis, Takeda, Roche, Pfizer, Bristol-Myers, Daichii-Sankyo, Lilly and Novo-Nordisk.
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