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PLCB4 (phospholipase C beta 4)

Written2020-12Roberto Brusamolino, Alessandro Beghini
University of Milan, Department of Health Sciences, Milan Italy rbrusamolino@gmail.com; alessandro.beghini@unimi.it

Abstract The gene PLCB4 codes for the homonymous enzymatic protein PLCβ4, one of the four isoforms belonging to the PCLβ subfamily, a subcategory of the PLC (phospholipases C) family. The cDNA characterization, sub-chromosomal localization and polypeptide product prediction have been studied primarily in the human retina. Human PLCB4 is strictly related to the Drosophila gene PLC-NorpA, which is critical in photo-transduction. In the human retina tissue PLCB4 is pivotal in the intracellular transduction of several extracellular signals, but it has a large pattern of tissue expression and certainly plays an important general role in intracellular molecular signaling. Moreover, this gene is involved in embryonic development as one of the enzymes of the endothelin pathway. These functional aspects (high level eye expression and homeotic role) take account of the two main pathological conditions in which the gene is etiologically involved: 1) Uveal melanoma (UM). In UM, PLCB4 promotes tumorigenesis by a gain-of-function mutation that activates the pathway of GNAQ/GNA11, the genes of which PLCB4 is the downstream target 2) Auriculo-condylar syndrome. This uncommon craniofacial malformation syndrome is characterized by missense mutations of PLCB4, whose protein product is a core signaling component of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5-DLX6). PLCB4 gene mutations have been associated with various neoplasms and this is not surprising considering the involvement of the PLCs, as a group, in several cellular signaling pathways influencing cell proliferation, differentiation, migration and growth.

Keywords PLCB4, Phospholipase C beta 4, Phosphoinositide cycle , Phosphatidylinositol signaling system, Uveal Melanoma , Auriculocondylar Syndrome .

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)ARCND2
PI-PLC
PLC-beta-4
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4
phospholipase C, beta 4
phosphoinositide phospholipase C- beta-4
HGNC (Hugo) PLCB4
HGNC Previous namephospholipase C, beta 4
LocusID (NCBI) 5332
Atlas_Id 47059
Location 20p12.3-p12.2  [Link to chromosome band 20p12]
Location_base_pair Starts at 9069087 and ends at 9480808 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PLCB4.png]
 
  Figure 1. PLCB4 is located in the interval region 20p12.3-p12.2 (+ strand).
 
  Figure 2. From Alvarez RA et al., 1995: A) PLCB4 FITC-labeled probe = green; D20Z1 rhodamin-detected CEP probe = red; B) PLCB4 FITC-labeled probe giving yellow signal on propidium iodide-colored chromosome 20 (R banded).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note The PLCB4 gene (HGNC ID: 9059) is part of a large group of human phospholipases (42 genes) in which PLCB4 is one of 19 genes forming the subgroup "C2 domain containing phospholipases". This subgroup includes 5 different phospholipases A2 and 14 phospholipases C (PLCsβ1-4, PLCsδ1-3, PLCε, PLCγ1-2, PLCη, PLCζ, PLC like1, PLC like2). Therefore, PLCB4 is the fourth of the PLCβ genes which collectively produce 4 related proteins (isoenzymes). Functionally, it is a member of the phosphatidylinositol signaling system, which is part of the signal transduction network, a critical component of the cell machinery involved in 'Environmental Information Processing (KEGG)'. The PLCB4 hortolog is conserved in 259 species including chimpanzee, dog, mouse, zebrafish, fruit fly, and C. elegans. A summary about this gene is available at NCBI Gene ID 5332 supplemented by the primary source HGNC:9059 that enumerates genetic, biochemical, clinical and bibliographic links.

DNA/RNA

Note The human PLCB4 cDNA sequence (3840 bp) has been identified in 1995 (Alvarez RA et al., 1995) starting from the cDNA of a human fetal retina library. Gene physical location (mapping): 9.068.678 (variant 4 isoform a) or 9.069.087 (variant 1 isoform a) to 9480808. (NCBI Gene ID 5332).
 
  Figure 3. Image modified from NCBI; Gene ID 5332. List of the main transcripts variants is reported. The variant 2 lacks an alternate in-frame exon in the central coding region, compared to variant 3. The complete exon combination of the 5' UTR for this variant has not been determined. The resulting isoform (b) lacks an internal segment, compared to isoform c (NM_182797.3).
Description DNA Sequence: assembly accessions at: 1-NCBI Reference Sequence: NC_000020.11 (general sequence with variant details). https://www.ncbi.nlm.nih.gov/nuccore/NC_000020.11?report=genbank&from=9068678&to=9480808 2-NCBI Reference Sequence: NG_032790.2 (GCF_000001405.39) obtained from GRCh38.p13 (Genome Reference Consortium Human Build 38 patch release 13): variant 3 (isoform c). See link: https://www.ncbi.nlm.nih.gov/nuccore/NG_032790.2?from=5001&to=416763&report=genbank
Gene length: 412131 bp genomic DNA related to the transcript variant 4 isoform "a" (NM 001377134.2, NP 001364063.1, NC_000020.11) and 411722 bp variant 1 isoform "a" (NM 000933.4, NP 000933.4).
Exon number: 46 (Gene ID 5332)
Transcription 25 transcript variants have been identified (NCBI - Gene ID 5332). Variants 1, 4 and 5 code for the isoform product "a" (1194 aa), variants 2 and 6 code for the isoform product "b" (1175 aa), variants 7 and 8 code for the isoform product "d" (1206 aa) and the variant 3 code for the isoform product "c" (1187 aa).

Protein

Description The 3D protein structure is mainly undetermined. The three-dimensional structure of the Y and C2 domains of PLCβ4 and a complete graphic representation of the very similar homologous protein PLCβ3 is provided at the following SWISS-MODEL link: https://swissmodel.expasy.org/repository/uniprot/Q15147?csm=AB2C8EB99EF57357
The PLCβ subfamily is distinguished by a C-terminal extension (≈ 400 aa) with highly conserved N-terminal segments (C-terminal domain [CTD] including: proximal CTD, a CTD linker 28-61 aa long, distal CTD with coiled-coil structure and a length of 300 aa). (Lyon AM and Tesmer JJG, 2013).
PLCβ4 protein exists in different isoforms. Four isoforms are produced by alternative splicing and it is considered as reference sequence the isoform 2 (UniProtKB identifier Q 15147-1). This variant is characterized as follows: A) Length=1175 aa B) M.W.=134,4 KDa. Isoform 3 is 1194 aa (identifier Q15147-4).
All the PLCβ4 isoforms are characterized by a similar domains architecture and by the same enzymatic catalytic core involved in the PIP2 hydrolysis (spanning from N terminus to the end of C2 domain).
The structural protein elements from N terminus to C terminus are listed below (Lyon AM and Tesmer JJG, 2013; Owusu Obeng et al., 2020; Nakamura Y and Fukami K, 2017):
1- PH (pleckstrin homology): regulatory domain, binding site for PtdIns(4,5)P2 (Owusu Obeng et al., 2020). N-end of PH corresponds to the start of the catalytic core.
2- EF (E and F helices of parvalbumin) hand repeats (four tandem): involved in GTP hydrolysis induced by Gαq.
3- PIPLC_X-box (phosphatidylinositol-specific phospholipase X-box domain) from 313 to 463 position (151 aa).
4- X-Y linker. The length of this element varies significantly in the different isoforms.
5- PIPLC_Y-box (phosphatidylinositol-specific phospholipase Y-box domain) from 565 to 681 position (117 aa).
6- C2 (C2 domain) from 684 to 809 position (126 aa). Intra- and intermolecular regulatory binding site and in particular for Ca++-dependent membrane attachment. C-end of C2 corresponds to the end of the catalytic core.
7- proximal CTD is the site of Gαq binding.
8- CTD linker. Length and sequence varying in different isoforms
9- distal CTD is involved in membrane binding
PIPLC_X-box, X-Y linker and PIPLC_Y-box together contribute to form the so-called triose phosphate isomerase (TIM)-like barrel domain. The TIM-like barrel is divided in the 2 halves X and Y by the X-Y linker and is home of the Ca++ dependent active site. X-box and Y-box are two regions of homology typical of all eukaryotic PIPLC. In all different isoforms the TIM-like barrel has the same relative position in the sequence (NH2-X-Y-COOH) with possible modification of spacing. They are the most relevant part of the catalytic site (Jiang H et al., 1996; Rhee SG and Choi KD, 1992).
 
  Figure 4. Domain diagram of PLCβ isozymes including splice variants. Catalytic core (PIP2 hydrolysis effector) extends from N terminus to the end of C2 domain in all isoforms. The length of the X-Y linker is a specific feature of each isoform, whereas length and sequence of the CTD linker and the C terminus differentiate in each splice variant. The CTD domain is typical of the PLCβ subfamily (Lyon AM and Tesmer JJG, 2013).
Expression Retina is the tissue where PLCB4 is mostly expressed although 222 anatomical sites and tissues show PLCB4-mRNA expression as observed by in situ techniques. Among them can be noted cerebellum, peripheral nervous system, parotid gland, colonic glands, and dermal papilla cells for the mRNA abundance (Genevisible Q15147). Other reported localizations are: pons cerebri, medulla and plasmacytoid dendritic cells.
Localisation Main subcellular location is to microtubules and additionally to nucleoplasm (The Human Protein Atlas).
Function PLCB4 is responsible for a catalytic step in the phosphoinositide cycle signaling pathway, which is involved in the intracellular signal transduction. InsP3 (1D-myo-inositol 1,4,5-trisphosphate) translocates from the membrane to the cytoplasm, as a consequence of the reaction, releasing calcium ion (Ca++) from the cell stocks while membrane-bound DAG activates protein kinase C (PKC) upon Ca++ release (Owusu Obeng et al., 2020).
All PLCβ subtypes are activated via the classical G-protein pathway (Rhee SG and Bae YS 1997). GPCRs (heterotrimeric G-Protein-Coupled Receptors) activate PLCβs, including PLCB4, by virtue of coordinated intervention of Gq family proteins (Gq, G11, G14, G15, G16). The activation may be cell type-specific and dependent on variable external stimuli (Suh PG et al. 2008, Rebecchi MJ and Pentyala SN 2000, Balla T 2010).
Interactions:
Environmental information processing is one of the basic functions of the cell and the three cornerstones of this function in the cell are: 1- membrane transport, 2- signal transduction, 3-signaling molecules and interaction. Phosphatidylinositol signaling system and Wnt signaling pathway both are involved in signal transduction and evidence has emerged of complex relationships between them. Two effective pathways for Wnt signals are known: 1- Canonical (cell fate determination), 2- Non-canonical (cell movement and tissue polarity). As it pertains to the links between Wnt signaling and PLCs, it is noteworthy that non-canonical Wnt signals are transduced to the Ca ++-dependent ( NLK and NFAM1 (NFAT)) signaling cascades through FZD family receptors with the intervention of coreceptors ( ROR2 and RYK). This transduction modality requires PLCs intervention in order to produce the two second messengers InsP3 and DAG (see figure 6).
 
  Figure 5. The diagram illustrates the catalytic steps related to the PLCβ4 molecular function.
Homology PLCB4 is conserved in Bilateria. NCBI database HomoloGene (8471) enumerates homolog PLCB4 genes in Vertebrates (chimpanzee, macaque, dog, cow, mouse, rat, chicken, zebrafish, frog) and Invertebrates (fruit fly, mosquito, C. elegans) but hundreds of different organisms are listed among those with a hortolog gene of PLCB4 (NCBI identifier: ortholog_gene_5332; and OrthoDB v10.1 database identifier Group 50317at33208 at Metazoa level).
 

Mutations

Note PLCB4 is affected by pathogenic germinal and somatic mutations. A detailed overview of mutational events is available in the database BioMuta under the UniProt identifier Q 15147. Given the large number of cancer-related mutations of still undefined meaning we focus here on the mutations linked to specific nosological entities by known pathogenic mechanism.
Germinal Missense mutations in Auriculo-Condylar Syndrome (A.C.S.) : PLCB4 (MIM 600810).
variant c. 986A>C (p.Asn329Ser); variant c.1861C>T (p.Asn>621Cys); variant c.1862G>A (p.Arg621His); variant c.1868A>G (p.Tyr623Cys); variant c.1948A>C (p.Asn>650His). All mutations spare the catalytic domain but compromise the substrate binding efficiency of the enzyme. It has been shown a dominant-negative effect of PLCB4 mutations that leads to downregulation of DLX5 and DLX6 genes (endothelin pathway), effectors of mandibular patterning and strongly under-expressed (6 and 8-fold respectively) in mandibular osteoblasts of A.C.S. patients (Rieder MJ et al., 2012).
Somatic See single entities

Implicated in

Note Since the beginning, given the link of the Drosophila homologous gene norpA with altered photo-transduction and retinal degeneration (Bloomquist BT et al. 1988), PLCB4 was suspected of being responsible for a similar pathology in humans. So far it has not been shown that alterations of PLBC4 are responsible for a precise nosological entity affecting human retina, though there is proof of the importance of the gene in the physiology of vision (Jiang H et al. 1996). Unexpectedly, the gene was found mutated in the Auriculo-condylar Syndrome (Rieder MJ et al, 2012), a cranio-facial malformation characterized by mandibular-maxillary homeotic transformation. These extremely rare, de novo PLCB4 mutations lead to an impairment of the endothelin-1-distal-less homeobox 5 and 6 ( EDN1 -DLX5/DLX6) pathway, known for its importance in mandibular development of other species. PLCB4 is currently known as an important gene for the development of the first and second pharyngeal arches in embryo.
Phosphoinositides are chemically phospholipids and are the specific substrate of all PLCs, including PLCB4. Phosphoinositides have an established role in cancer development as they can affect proliferation, survival and spreading of cancer cells. The two 'second messengers' produced by PLCB4, InsP3 and DAG, are responsible for the Ca++ increase in the cytosol and the activation of Protein Kinase C (PKC) respectively. Both are factors capable of influencing neoplastic growth. PIs (phosphoinositides) and their metabolic enzymes modulate apoptosis, proliferation, differentiation, vesicular trafficking, cell adhesion, and cell migration (Owusu Obeng et al., 2020).
  
Entity Uveal melanoma
Disease Uveal melanoma (UM) is the first intraocular malignancy by frequency and is affected by poor prognosis with a 50% metastatic rate (Afshar AR et al, 2019). In 2015 (Johansson P et al., 2015) PLCB4 was added to the list of driver genes for UM ( GNAQ, GNA11, CYSLTR2, EIF1AX, SF3B1, BAP1). PLCB4, GNAQ and GNA11 are G-protein pathway-associated and they belong to the same Gαq pathway. A recurrent mutation (Asp630Tyr) in the sequence of Y domain was found in 2 out of 28 samples by whole genome sequencing (n=14) or whole exome sequencing (n=9). Cases with a range of different mutations affecting the same codon D630 (Asp630) have been reported in the medical literature (Asp630Val; Asp630Fen; Asp630Asn) (Johansson P et al., 2015). PLCB4 is normally activated by GNAQ interaction (PLCβ4 is the downstream effector of Gαq signaling) (Moore AR et al., 2016). Considering that the mutations in UM are mutually exclusive, it can be inferred that PLCB4 hotspot mutation is a recurrent gain-of-function mutation activating the same pathway involving GNAQ/GNA11. Mutations of the genes of this pathway account for 98% of UM cases. PLCB4 mutation frequency is 2,5% and it could be a target for specific inhibitors (Chua V et al., 2017). In order to counter the PLCB4 activity the PKC-inhibitor LXS196 has been tested with partial responses in metastatic UM (Violanti SS et al., 2019). It is remarkable that derangement of the Gαq signaling (heterotrimeric G proteins) is specific for UM and not for cutaneous malignant melanoma (CMM). PLCB4 D630Y (Asp630Tyr) mutation is rarely detected in primary leptomeningeal melanocytic tumors (PLMTs or "melanocytomas"). This mutation helps in the differential diagnosis between PLMTs and metastasis to central nervous system by cutaneous malignant melanoma. PLCB4 D630Y (Asp630Tyr) is always absent in cutaneous melanoma and its metastases and this differentiates the two tumors, which is clinically relevant given the frequently benign nature of the PLMTs (van de Nes et al., 2017).
A very recent observation has drawn attention to the causal link between ocular melanocytosis and UM. Ocular melanocytosis strongly predisposes to UM (Singh AD et al. 1998) with risk of UM increased from 1 in 230,000 to 1 in 400. A case report focusing on this clinical correlation (Durante MA et al., 2019) refers to a patient affected by UM arose from a pre-existing ocular melanocytosis. Slightly less than 25% of the melanocytosis cells and 100% of the melanoma cells revealed to be affected by PLBC4 D630Y in the absence of germinal mutation. Genetic complete characterization showed that PLCB4 mutation was the initiating, but not the transformation factor in the described case report. In the context of melanocytosis a condition of loss of heterozygosity arising in the chromosome 3 likely represents the "threshold event" on the way to malignant transformation of the PLCB4-mutated clone.
  
  
Entity Acute Myeloid Leukemia (AML)
Note AML, together with brain tumors, holds the primacy among the causes of infant death worldwide. Survival has improved in recent years (Curtin SC et al, 2016) but the overall survival (OS) is still relatively low and there is a need to identify molecular parameters of prognostic and therapeutic significance. This is the purpose of a recent study (Wu S et al., 2019) that investigated the prognostic value of PLCB4 overexpression in pediatric leukemia.
Disease In silico analysis of expression profiles obtained from the database TARGET on a sample of 285 pediatric de novo AML (pAML), classified patients as low-PLCB4 and high PLCB4 group. Overall it emerged that PLCB4 overexpression independently predicts a poor prognosis in case of chemotherapy but not in case of stem cell transplantation (SCT) in CR1 (complete remission after first cycle).
Survivors at 5-years follow-up had a median value of PLCB4 mRNA expression significantly lower with an overall survival of 60.7 months vs 28.5, and an event-free survival of 16.3 months vs 12.5. Patients with long-term CR and lower relapse rate had a median value of PLCB4 mRNA expression significantly low. Moreover, white blood count correlates positively with PLCB4 expression observing the highest PLCB4 expression in CD34+CD38- cells compared to CD34-CD38+ or CD34+CD38+ cells (Wu S et al., 2019). These results are confirmed by other study (Zheng GH et al, 2009) who found upregulation of PLCB4 in an AML cell-line (HL-60/MDR) with multi-drug resistance. Furthermore, there are other studies where PLCB4 appears to behave in the opposite way, for example in the case of PLCB4 upregulation manifested by breast cancer patients with complete response to chemotherapy (Li Y et al., 2017).
  
  
Entity T-Acute Lymphoblastic Leukemia (T-ALL)
Disease In addition to AML there are hints that PLCB4 may be involved as well in pediatric T-ALL (Haider Z et al., 2019). A set of 216 genes was overexpressed in CIMP-negative (CpG Island methylator phenotype) subgroup, characterized by a worse prognosis in T-ALL (Borssen M et al., 2013), while 548 genes were overexpressed in CIMP+. PLCB4 shows significantly higher expression in CIMP+ T-ALL, associated with better prognosis, and this is true even when compared to normal T cells. No in-depth analysis was carried out in this study regarding the molecular mechanism of this overexpression and its possible consequences on the cell fate.
  
  
Entity Breast Cancer
Disease Primary operable breast cancer undergo neoadjuvant chemotherapy (NST = Neoadjuvant Systemic Therapy) as a standard option. The response to NST can give information on the likelihood of cancer recurrence and survival, in this way the best chance would be to have predictors of NST response because patients with low probability of NST response could be spared unuseful toxic treatment. Various biological markers have been investigated for this purpose such as negative hormone receptors status, ERBB2 (Her2/Neu) positivity, TOP2A (Topoisomerase IIα), BCL2 loss (Kaufmann M et al., 2007).
Studies were conducted to define a gene expression profile linkable to NST response. Li and coworkers analyzed two small groups (3 vs 3) of breast cancer patients on the base of complete or not-complete pathologic response (NST-responding or NST-non responding) to chemotherapy (Li Y et al., 2017). A set of 673 differentially expressed genes (DEG) emerged and a pathway enrichment analysis was performed. Results identified a set of 18 genes, including PLCB4, that effectively stratified the sample in responders and non-responders. Four out of these 18 genes are considered key genes on the base of their protein-protein interaction pattern (PLCB4, ADCY6, CNR1, MAPK14). In particular upregulated PLCB4 is positively involved in pathological complete response to chemotherapy, intervening in multiple pathways (renin secretion, gastric acid secretion, gap junction, inflammatory mediator regulation of TRP channels, retrograde endocannabinoid signaling, melanogenesis, cGMP-PKG signaling pathway, calcium signaling pathway, chemokine signaling pathway, c-AMP signaling pathway, rap1 signaling pathway). At least two other isozymes of the PLCB family ( PLCB1 and PLCB2) are reported as possible prognostic markers (Cai S et al., 2017). Overexpressed PLCB4 and PLCB2 have been associated with multidrug resistance (MDR) in breast cancer. The identification of differentially expressed genes between the breast cancer cell lines MCF-7 and MCF-7/MDR cells confirmed PLCB4 as an overexpressed hub gene (Yang M et al., 2018).
PLCB4 is one of the primary target genes of TFAP2C, an important transcription factor playing a role in the oncogenesis of breast cancer. In mammary tumors TFAP2C induces a very large number of genes belonging to different functional groups, including a set of intracellular signaling genes such as PLCB4 (Woodfield GW et al. , 2010).
  
  
Entity Colon adenocarcinoma (COAD)
Disease There are molecular differences between right colon adenocarcinoma (RCOAD) and left colon adenocarcinoma (LCOAD), RCOAD has a worse prognosis than LCOAD (Han J et al., 2020).
Genomic data of 9 cases of RCOAD and 9 of LCOAD have been recovered from open-source platform GEO (Gene Expression Omnibus-GEO database), selection of DEGs (differentially expressed genes) between these two groups of colon cancers identified 286 DEG genes. Construction of protein-protein interaction network of the DEGs and identification of hub genes have been performed. PLCB4 resulted downregulated in RCOAD compared to LCOAD. A gene set was therefore able to differentiate between RCOAD and LCOAD. Despite the fact that PLCB4 belongs to the hub gene group and is markedly downregulated in RCOAD no association with pathological stage nor statistically significant effect on overall survival have been demonstrated and this excludes a causal role of PLCB4 in the worse prognosis of RCOAD vs LCOAD.
  
  
Entity Non-small cell lung carcinoma (NSCLC)
Disease Overexpression of PLCB4 has recently been associated with a better prognosis of lung adenocarcinoma. A in silico study (Zhang T et al., 2019) analysed a cohort of 1926 NSCLC (non-small cell lung carcinoma) patients starting from gene expression and survival values. It emerged that overexpression of PLCB1, PLCB2, and PLCB3 are related to poor overall survival of all NSCLC patients and poor prognosis of adenocarcinoma. On the contrary PLCB4 overexpression improves the OS of adenocarcinoma patients. Of interest, the correlation analysis of PLCB family found that these four genes are linked to each other in a complex network. Conclusions suggested that not only PLCB4 but the PLCB subfamily as a whole has a possible use in defining the prognosis of the NSCLC patients.
Disruption of Gq signaling (the pathway including PLCB4) by a competitive inhibition mechanism reduces the basal activity of PKC and promotes inhibition of small cell lung cancer growth (Beekman A et al, 1998).
  
  
Entity Mesothelioma
Disease Evidences on the relationship between mesothelioma and PLCB4 derives from the study of the effect of PLCB4 knockdown in mesothelial cell lines (Kakiuchi T et al., 2016).
Comparative gene expression analysis reveals overexpression of PLCB4 in YAPS127A-transformed cells vs control cells (Kakiuchi T et al., 2016). Moreover YAP knockdown (Mizuno T et al., 2012) downregulates PLCB4 in Hippo-disrupted mesothelioma cell lines and PLCB4 knockdown inhibits the cell growth in 8 mesothelioma cell lines (4 YAP-active and 4 YAP-non active) only if they are YAP active. These effects are evidence of the activating function of YAP on its downstream effector gene PLCB4. PLCB4 is critical for proliferation and anchorage- independent growth of YAP-dependent mesothelioma cells and represents a potential pharmacological target in YAP-active mesotheliomas. In addition to Hypo other pathways are involved in mesothelioma molecular mechanisms such as Wnt (Guo G et al., 2015) and Ras/mitogen activated protein kinase. Wnt can be affected by NF2 (neurofibromin 2) knockdown and dasatinib, a tyrosine kinase inhibitor antagonizing the YAP- CTNNB1 (β catenin)- TBX5 complex, impairs growth of NF2-knocked cells (Kakiuchi T et al., 2016).
  
  
Entity Glioblastoma
Disease In consideration of the finding that copy number loss commonly affects genes involved in phosphoinositide signaling pathway, e.g. PTEN and PK3C2B (Kim YW et al., 2013; Gu Y et al., 2013) a number of different phosphoinositide pathway genes (45 genes) were investigated by in silico analysis. Copy number amplification of the chromosome 20, that carries PLCB4 and its isoform gene PLCB1, was detected in 30% of the total 638 tumour samples analysed. STRING software approach confirms that phosphoinositide pathway gene products shows high interaction level. Loss or gain of one gene can change the pattern of the phosphoinositide network as a whole. The conclusion is suggested that general analysis of the phosphoinositide pathway can shed light on tumoral biochemical pathways to drug resistance (Waugh MG, 2016).
  
  
Entity Gastrointestinal stromal tumor (GIST)
Disease The search for potential new molecular targets is justified by the very frequent phenomena of resistance that occur in the therapy of GISTs through Imatinib administration (Debiec-Rycther M et al., 2005). A set of 77 genes involved in lipid catabolic processes was subjected to in silico screening by analysis of a population of 350 GISTs. PLCB4 resulted the top-ranking gene being overexpressed in 30% of total cases. Association of overexpression with high-risk cases and presence of metastasis was very strict. Moreover, PLCB4 copy number variations (amplification or polysomy) results in PLCB4 overexpression in 50% of cases (Li CF et al., 2017). PLCB4 copy gain and protein overexpression are independently a robust marker of shorter DFS (disease free survival) and worse prognosis in which amplification has a more negative impact than polysomy. The fact that around half of the cases with PLCB4 overexpression lack copy number gain still requires an explanation. In this viewpoint a molecular mechanism alternative to copy number amplification could be the positive regulatory effect of YAP1 on PLCB4. Accordingly, YAP1 knockdown significantly reduces PLCB4 mRNA and PLCB4 protein expression. YAP1 knockdown and silencing of PLCB4 by RNA interference both induce proliferative slowdown of GIST cells. Copy gain and protein overexpression being not equivalent prognostic markers it is advisable to complement PLCB4 immunostaining with PLCB4-specific FISH assay.
  
  
Entity Hepatocellular carcinoma (HCC)
Disease HCC is a poor prognosis cancer with a 12% rate of 5-years survival. There is need of innovative biomarkers with relevance in prognosis, early diagnosis and targeted therapy. The marked structural and functional similarities of isoenzymes belonging to the PLCBs subfamily justify their collective analysis in a recent HCC study (Wang X et al., 2019). Molecular genetics and clinical data was obtained from a public dataset including 212 patients. PLCB4 was expressed at the same level in tumor and normal tissue although transcriptional levels were higher in cancer cells. PLCB4 was found to have no diagnostic significance unlike the other members of the subfamily (PLCB1 and PLCB2 more than PLCB3). Only PLCB1 expression was negatively associated with OS and RFS. The other 3 genes of the subfamily, PLCB4 included, did not affect the prognosis.
This study seems to suggest that more interesting results can be obtained by studying the PLCB gene network rather than individual members alone.
  
  
Entity Hemangioblastoma (HB)
Disease HB is an uncommon vascular tumour of benign nature affecting the central nervous system. The familial subtype of HB occurs in Von Hippel-Lindau disease and the typical mark of this tumour subtype is a germinal alteration of the VHL gene. Different genetic anomalies contribute to the HB genesis due to the fact that only 4-25% of sporadic case are associated to a VHL gene somatic mutation. A whole-exome study explored the existence of additional genetic alterations in a sample of 11 patients, six affected by a sporadic form and five affected by a familial form (Ma D et al., 2017).
270 somatic single nucleotide variations (SNV) and a large number of copy number variation (CNV) were found. The observation that many of the genes harboring CNVs are members of different tumour-related pathways suggests that they can somehow influence the disease susceptibility. In sporadic tumours five genes, including PLCB4, were affected by CNVs. In familial tumours three genes had CNVs. In particular PLCB4-copy number deletion was present in 2 patients and amplification in 4 patients. Possible underlying mechanisms relating PLCB4-CNVs to HB tumorigenesis was not investigated.
  

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Citation

This paper should be referenced as such :
Brusamolino R, Beghini A
PLCB4 (phospholipase C beta 4);
Atlas Genet Cytogenet Oncol Haematol. in press


External links

Nomenclature
HGNC (Hugo)PLCB4   9059
Cards
AtlasPLCB4ID47059ch20p12
Entrez_Gene (NCBI)PLCB4    phospholipase C beta 4
AliasesARCND2; PI-PLC
GeneCards (Weizmann)PLCB4
Ensembl hg19 (Hinxton)ENSG00000101333 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000101333 [Gene_View]  ENSG00000101333 [Sequence]  chr20:9069087-9480808 [Contig_View]  PLCB4 [Vega]
ICGC DataPortalENSG00000101333
TCGA cBioPortalPLCB4
AceView (NCBI)PLCB4
Genatlas (Paris)PLCB4
SOURCE (Princeton)PLCB4
Genetics Home Reference (NIH)PLCB4
Genomic and cartography
GoldenPath hg38 (UCSC)PLCB4  -     chr20:9069087-9480808 +  20p12.3-p12.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PLCB4  -     20p12.3-p12.2   [Description]    (hg19-Feb_2009)
GoldenPathPLCB4 - 20p12.3-p12.2 [CytoView hg19]  PLCB4 - 20p12.3-p12.2 [CytoView hg38]
ImmunoBaseENSG00000101333
Genome Data Viewer NCBIPLCB4 [Mapview hg19]  
OMIM600810   614669   
Gene and transcription
Genbank (Entrez)AK025027 AK054754 AK057634 AK122699 AK307482
RefSeq transcript (Entrez)NM_000933 NM_001172646 NM_001377134 NM_001377135 NM_001377136 NM_001377142 NM_001377143 NM_182797
Consensus coding sequences : CCDS (NCBI)PLCB4
Gene ExpressionPLCB4 [ NCBI-GEO ]   PLCB4 [ EBI - ARRAY_EXPRESS ]   PLCB4 [ SEEK ]   PLCB4 [ MEM ]
Gene Expression Viewer (FireBrowse)PLCB4 [ Firebrowse - Broad ]
GenevisibleExpression of PLCB4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5332
GTEX Portal (Tissue expression)PLCB4
Human Protein AtlasENSG00000101333-PLCB4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)PLCB4
Human Protein Atlas [tissue]ENSG00000101333-PLCB4 [tissue]
HPRD02885
Protein Interaction databases
BioGRIDPLCB4
STRING (EMBL)PLCB4
ZODIACPLCB4
Ontologies - Pathways
Litterature
PubMed51 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXPLCB4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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