The emerging roles of GPRC5A in diseases

Abstract

The 'Retinoic Acid-Inducible G-protein-coupled receptors' or RAIG are a group comprising the four orphan receptors GPRC5A, GPRC5B, GPRC5C and GPRC5D. As the name implies, their expression is induced by retinoic acid but beyond that very little is known about their function. In recent years, one member, GPRC5A, has been receiving increasing attention as it was shown to play important roles in human cancers. As a matter of fact, dysregulation of GPRC5A has been associated with several cancers including lung cancer, breast cancer, colorectal cancer, and pancreatic cancer. Here we review the current state of knowledge about the heterogeneity and evolution of GPRC5A, its regulation, its molecular functions, and its involvement in human disease.

Keywords: GPRC5A; RAI3; cancer; dual-behavior; oncogene; tumor suppressor.

Figure 1. GPRC5A expression

A. Levels of expression of mRNA in different organs and tissues. mRNA expression is measured by using RNA-seq. The expression levels are plotted as number of Fragments Per Kilobase of Exon Per Million Fragments Mapped. B. Expression of protein in different organs and tissues in both normal and cancer. Protein levels are measured by using immunohistochemistry. Different intensities indicate different expression levels. The Figure was compiled using data is from The Human Protein Atlas http://proteinatlas.org/.

Figure 2

A. Alignment of human GPRC5A across several species. Identical (*) and conservatively substituted (:) amino acids are indicated. Gaps are shown with “-” whereas putative TM segments are over-lined. B. Alignment of the four receptors from the human class C group 5. Identical (*) and conservatively substituted (:) amino acids are indicated. Gaps are shown with “-” whereas putative TM segments are over-lined.

Figure 3. Chromosomal locus, gene architecture and transcription factor binding information

A. GPRC5A gene (ENSG00000013588) location is chromosome 12:13,030,138-13,084,449. B. RAR/RXR binding site, CREB binding site, TP53 binding sites, BRCA1 binding sites, FOS/JUN binding sites, and MYC binding site are located between 13,043,716 and 13,044,596. C. GPRC5A mRNA (ENST00000014914) is spliced from the region between 13,043,716 and 13,070,871. Transcription factor information was compiled using data from the ENCODE project predictions from JASPAR [92].

Figure 4. A systemic view of GPRC5A's activity

In the nucleus, TP53 inhibits GPRC5A gene transcription by binding to GPRC5A's promoter region. On the other hand, cAMP promotes GPRC5A's transcription by binding to the latter's promoter region along with cAMP receptor protein (CRP). RA binding to RAR/RXRs results in dissociation of co-repressor and recruitment of co-activator proteins that in turn promotes GPRC5A gene transcription. In the cytosol, GPRC5A mRNA is targeted by miR-103a-3p, resulting mainly in mRNA degradation. GPRC5A protein is phosphorylated at S301 and S345 during mitosis by cyclin-dependent kinases. In addition, R158 in GPRC5A is likely glycosylated in vivo. Also, L285, L333, L348 and L353 at the C-terminus of GPRC5A might be ubiquitinated by the HRD1/Cullin-Ring E3 ligase complex. With regard to downstream signaling pathways, GPRC5A could promote SOCS3 and BRCA1 expression while inhibiting NF-κB and Gsα expression, but details of this mechanism are lacking. GPRC5A may also inhibit UBE2C, FEN1, MCM2 and CCND1 expression based on previously reported indirect evidence [64]. Arrows in this diagram represent up-regulation or activation. T-joints indicate down-regulation or inhibition (direct evidence) whereas dashed T-joints indicates the available evidence is indirect. Interrupted lines indicate a connection that involves one or more intermediate pathways.