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GRHL2 (grainyhead like transcription factor 2)

Written2017-08Gizem Kars, Mesut Muyan
Middle East Technical University, Department of Biological Sciences, ankaya 06800, Ankara, Turkey; gizem.kars@metu.edu.tr; mmuyan@metu.edu.tr

Abstract A mammalian homolog of Drosophila Grainyhead protein, Grainyhead like 2 belongs to the Grainy Head-Like Proteins/CCAAT binding protein, GRH/CP2 family which is conserved from drosophila to mammals (Venkatesan, 2003). In mammals, there are 3 members of the family, GRHL1-3, the expression of which exhibit differential spatiotemporal expression patterns during development and in adult tissues. The GRHL family members are essential developmental transcription factors in epithelial cell morphogenesis/differentiation and in tumorigenesis (Stramer and Martin, 2005; Werth et al., 2010). Although the family members have common molecular and biological functions during development, they rarely exhibit functional redundancy due to different gene targets (Boglev et al., 2011). GRHL2 can act as a tumor-suppressor or oncogene depending upon tissue of expression.

Keywords GRHL2; Transcription factor; development, keratinocyte; differentiation; cancer

(Note : for Links provided by Atlas : click)

Identity

Alias_namesDFNA28
TFCP2L3
deafness, autosomal dominant 28
transcription factor CP2-like 3
grainyhead-like 2 (Drosophila)
Alias_symbol (synonym)FLJ13782
BOM
Other aliasTranscription Factor CP2-Like 3 (TFCP2L3)
Brother Of Mammalian Grainyhead (BOM)
Grainyhead-Like Protein 2 Homolog ALIAS Deafness Autosomal Dominant 28
HGNC (Hugo) GRHL2
LocusID (NCBI) 79977
Atlas_Id 50630
Location 8q22.3  [Link to chromosome band 8q22]
Location_base_pair Starts at 101492439 and ends at 101669724 bp from pter ( according to hg19-Feb_2009)  [Mapping GRHL2.png]
 
  Orange arrow indicates the GRHL2 (NC_000008.11) location on chromosome 8 on positive strand shown as black line. Green arrow indicates NCALD, the closest gene to GRHL2.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Note The GRHL2 located on chromosome 8q22.3 is on the forward strand and spans 177287 bp on the genome. It has 16 exons. The primary mRNA transcript 1 (NM_024915.3) is 5231 bp in length and contains an open reading frame of 1878 bp (NCBI ,2017).
 
  Exons are shown in boxes; lines indicate introns. The encoding exons are in green. The start codon ATG and stop codon TGA are shown.
Description The human GRHL2 gene is located on chromosome 8 and contains 16 exons.
Transcription It appears that an internal 5' splicing site within the first exon of GRHL2 generates an alternate GRHL2 mRNA (NM_001330593) with a 203-base deletion containing the first Met encoding AUG codon in its 5'-end. This results in the utilization of the second AUG within exon 2 giving rise to an amino-terminally truncated (16 residues) GRHL2 isoform (NP_001317522.1), GRHL2v (17-625) that displays a disrupted transactivation function.

Protein

Note GRHL2 variant 1 transcript encodes a 625 amino acids (aa) long protein (NP_079191.2). Based on GHRL2 and its Drosophila homolog GRH, the protein isoform 1 contains transcription activation domain at the amino-terminus (1-93 aa) and a large CP2 Transcription Factor domain between 119-438 aa that is responsible for DNA binding as well as a dimerization domain at the carboxyl-terminus (Attardi and Tijan, 1993, Kokoszynska et al., 2017; Uv, Thompson and Bray, 1994). Resulting from the alternative splicing of GHRL2 transcript, GRHL2 isoform 2 lacks the first 16 amino-acids and is a 609 aa long protein (NP_001317522.1). GRHL2 isoform is reported to counteract the oncogenic potential of GRHL2 isoform 1 by acting as a dominant negative manner (Werner et al., 2013).
Proteomic analyses also suggest that GRHL2 is a phosphoprotein in various normal and cancerous tissues as well as in cell lines (Mertins et al., 2016).
 
  GRHL2, composed of 625 aa, contains a transactivation domain between 1-93 aa; a CP2 domain between 119-438 aa responsible for DNA binding and a dimerization/oligomerization domain at the carboxyl-terminus.
Description GRHL2 protein is a transcription regulator that has a conserved CP2 domain.
Expression In human adults, GRHL2 is expressed in the placenta, brain, kidney, prostate, thymus, lung, salivary gland, mammary gland, digestive tract, and pancreas (Wilanowski et al., 2002; Peters et al., 2002).
It is also reported that MIR194 and MIR217 inhibit the cellular proliferation and promote cellular differentiation by targeting the GRHL2 translation (Yu et al., 2017; Zhu et al.,2016).
Localisation GRHL2 is localized primarily in the nucleus (Chen et al., 2010; Petrof et al., 2014). GRHL2 is also observed to be localized in the cytoplasm and at the inner cell membrane (Petrof et al., 2014).
Function GRHL2 is a transcription factor. The GRHL2 encodes a 71 kDa protein functions as DNA binding protein that interacts with permutations of the consensus sequence 5'-AACCGGTT-3' (Werner et al., 2013). GRHL2 appears to act as transcription repressor and/or activator depending on chromatin context of target genes (Mehrazarin.et al., 2015).
Observations with experimental animal models indicate that the knock-out of, or nonsense mutations in, the mouse Grhl2 gene results in embryonic lethality due to defects in neural tube closure, epithelial morphogenesis, and barrier formation by de-regulation of cell junction protein expressions (Werth et al.,2010; Pyrgaki, Liu and Niswander, 2011). This finding emphasizes the essentiality of Grhl2 for epithelial and neural morphogenesis during embryogenesis.
GRHL2 is also implicated in the carcinogenesis of various tissues and organs. Consistent with its role in epithelial morphogenesis, GRHL2 is shown act as tumor-suppressor by controlling the epithelial-mesenchymal transition (EMT), an essential characteristic of tumor progression (Wellner et al., 2009). In contrast, GRHL2 is also reported to act as an oncogene by promoting cell proliferation and survival (Cieply et al., 2013). Although underlying reasons are yet unclear, de-regulation of tissue/organ specific expression of the GHRL2 gene together with tissue/organ specific gene targets of GHRL2 is suggested to underlie the dual effects of GRHL2 on carcinogenesis (Wellner et al., 2009).
Homology GRHL2 is a conserved gene among vertebrates and in Drosophila.

Mutations

Note Tyr to His substitution at the position 398 and Ile to Lys at 498 of GHRL2 are observed in ectodermal dysplasia (Petrof et al., 2014). In addition, single nucleotide insertion at the position 1609 is reported to lead to frame shift and early stop codon in the encoding transcript (Peters et al., 2002).
Germinal Haploinsufficiency for GRHL2 implicated in non-syndromic sensorineural deafness- autosomal dominant type 28 (DFNA28), due to frameshift mutations and single nucleotide polymorphism in the gene (Van Laer et al., 2007), are associated with hearing loss. (Peters et al., 2002). These variations in the GRHL2 gene are suggested to likely result in deregulated gene expressions encoding for cell junction proteins and ion channels in the otic epithelial cells, which are important for the inner ear development and homeostasis (Han et al., 2011).
It is also reported that mutations in the GRHL2 sequences encoding DNA binding domain result in an autosomal-recessive ectodermal Dysplasia syndrome (Petrof et al., 2014).

Implicated in

  
Entity Breast cancer
Note GRHL2 is implicated to play a role in epithelial-mesenchymal transition (EMT) of breast cancer. It appears that increased expression of GHRL2 is inversely correlated with increased tumor stages and the presence of lymph node metastases (Cieply et al., 2012). Extending these observations, experimental studies using breast cancer cell models further suggest that the expression of GRHL2 is downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines, where it suppresses EMT, enhances anoikis sensitivity, and suppresses mammosphere generation. Moreover, it appears that the GRHL2 expression prevents tumor initiation in xenograft animal models and suppresses the emergence of phenotype indicative of cancer stem cell (Cieply et al.,2012).
  
  
Entity Esophageal cancer
Note Studies suggest that de-regulated expression of the GRHL2 gene is common in esophageal cancer. The expression of GRHL2 is observed to be higher in esophageal tumor tissue than that of in adjacent tissues (Shao et al., 2017). The level of GRHL2 expression appears also to be associated with tumor differentiation and to show correlation with lymph node metastasis and invasion depth.
  
  
Entity Gastric cancer
Note GRHL2 is suggested to be a tumor suppressor in gastric tissue. The GRHL2 expression and GRHL2 synthesis is reported to be reduced in gastric cancer compared to normal gastric tissues; it is therefore suggested that the down regulation of the GRHL2 expression contributes tumor invasion and metastasis (Xiang et al., 2008). Consistent with this, the GRHL2 overexpression appears to inhibit the invasion and migration of cell models derived from gastric cancer (Xiang et al., 2017).
  
  
Entity Prostate cancer
Note Based on gene expressions analyses, the GRHL2 expression is observed to be upregulated in prostate cancer (Paltoglou et al., 2017; Danila et al., 2014).
  
  
Entity Kidney cancer
Note Based on publically available data sets of 593 clear cell renal cell carcinoma (ccRCC) and 389 normal kidney samples and verification with patient samples, GRHL2 is found to be downregulated in tumor cells compared normal tissue. Moreover, GRHL2 expression observed to be associated with higher chances for disease relapse (Butz et al,. 2014). Extending these observations on tumor-repressor properties of GRHL2, experimental studies showed that silencing of GRHL2 expression in a non-tumorigenic kidney cell line results in an increased cell proliferation and increased resistance to apoptosis (Pawlak et al., 2017).
  
  
Entity Ovarian cancer
Note The overexpressed GRHL2, due to hypomethylation, is observed to be significantly higher in low malignant potential (LMP) and high-grade (HG) serous epithelial ovarian cancer (EOC) tumors compared with normal tissue. Cell lines modelling EOC display an invasive and metastatic phenotype (Faddaoui et al., 2017). The oncogenic potential of GRHL2 is further suggested by the observations that the suppression of GRHL2 inhibits the proliferation, migration and invasion in ovarian cancer cell models (Chung et al., 2016).
  
  
Entity Colorectal cancer
Note The expression of the GRHL2 is reported to be upregulated in colorectal cancer (CRC) samples compared to control non-tumorigenic tissue assessed with immunohistochemistry, qRT-PCR, and western blot analyses. It appears that elevated levels of the GRHL2 expression are associated with tumor progression due to higher levels of cell proliferation. Consistent with these observations, the repression of GRHL2 synthesis decreases the proliferation by inhibiting cell cycle progression of CRC cell models and impairs tumor growth in a xenograft mouse model (Quan et al., 2014).
  
  
Entity Cervical cancer
Note Analyses of cervical lesions of cancer patients indicate that the GRHL2 expression is diminished at both mRNA and protein level compared with normal tissue, which is also consistent with the expression analyses of cell lines derived from cervical cancer (Reyes et al., 2014).
  

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Citation

This paper should be referenced as such :
Kars G, Muyan M
GRHL2 (grainyhead like transcription factor 2);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/GRHL2ID50630ch8q22.html


External links

Nomenclature
HGNC (Hugo)GRHL2   2799
Cards
AtlasGRHL2ID50630ch8q22
Entrez_Gene (NCBI)GRHL2  79977  grainyhead like transcription factor 2
AliasesBOM; DFNA28; ECTDS; TFCP2L3
GeneCards (Weizmann)GRHL2
Ensembl hg19 (Hinxton)ENSG00000083307 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000083307 [Gene_View]  chr8:101492439-101669724 [Contig_View]  GRHL2 [Vega]
ICGC DataPortalENSG00000083307
TCGA cBioPortalGRHL2
AceView (NCBI)GRHL2
Genatlas (Paris)GRHL2
WikiGenes79977
SOURCE (Princeton)GRHL2
Genetics Home Reference (NIH)GRHL2
Genomic and cartography
GoldenPath hg38 (UCSC)GRHL2  -     chr8:101492439-101669724 +  8q22.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GRHL2  -     8q22.3   [Description]    (hg19-Feb_2009)
EnsemblGRHL2 - 8q22.3 [CytoView hg19]  GRHL2 - 8q22.3 [CytoView hg38]
Mapping of homologs : NCBIGRHL2 [Mapview hg19]  GRHL2 [Mapview hg38]
OMIM608576   608641   616029   
Gene and transcription
Genbank (Entrez)AK002034 AK023844 AK292853 AK296817 AK310221
RefSeq transcript (Entrez)NM_001330593 NM_024915
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)GRHL2
Cluster EST : UnigeneHs.690766 [ NCBI ]
CGAP (NCI)Hs.690766
Alternative Splicing GalleryENSG00000083307
Gene ExpressionGRHL2 [ NCBI-GEO ]   GRHL2 [ EBI - ARRAY_EXPRESS ]   GRHL2 [ SEEK ]   GRHL2 [ MEM ]
Gene Expression Viewer (FireBrowse)GRHL2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)79977
GTEX Portal (Tissue expression)GRHL2
Human Protein AtlasENSG00000083307-GRHL2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6ISB3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6ISB3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6ISB3
Splice isoforms : SwissVarQ6ISB3
PhosPhoSitePlusQ6ISB3
Domains : Interpro (EBI)CP2   
Domain families : Pfam (Sanger)CP2 (PF04516)   
Domain families : Pfam (NCBI)pfam04516   
Conserved Domain (NCBI)GRHL2
DMDM Disease mutations79977
Blocks (Seattle)GRHL2
SuperfamilyQ6ISB3
Human Protein Atlas [tissue]ENSG00000083307-GRHL2 [tissue]
Peptide AtlasQ6ISB3
HPRD10545
IPIIPI00016576   IPI00736700   IPI00981678   
Protein Interaction databases
DIP (DOE-UCLA)Q6ISB3
IntAct (EBI)Q6ISB3
FunCoupENSG00000083307
BioGRIDGRHL2
STRING (EMBL)GRHL2
ZODIACGRHL2
Ontologies - Pathways
QuickGOQ6ISB3
Ontology : AmiGOintronic transcription regulatory region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding  neural tube closure  cardiac ventricle morphogenesis  epithelial cell morphogenesis  epithelial cell morphogenesis  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  cell-cell junction  transcription from RNA polymerase II promoter  cell adhesion  brain development  cell proliferation  epidermis development  membrane  chromatin DNA binding  cell junction assembly  multicellular organism growth  embryonic digit morphogenesis  camera-type eye development  sequence-specific DNA binding  regulation of DNA methylation  regulation of DNA methylation  negative regulation of keratinocyte differentiation  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  embryonic cranial skeleton morphogenesis  positive regulation of telomerase activity  face development  lung lobe morphogenesis  lung epithelial cell differentiation  epithelial cell morphogenesis involved in placental branching  bicellular tight junction assembly  epithelium migration  
Ontology : EGO-EBIintronic transcription regulatory region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding  neural tube closure  cardiac ventricle morphogenesis  epithelial cell morphogenesis  epithelial cell morphogenesis  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  cell-cell junction  transcription from RNA polymerase II promoter  cell adhesion  brain development  cell proliferation  epidermis development  membrane  chromatin DNA binding  cell junction assembly  multicellular organism growth  embryonic digit morphogenesis  camera-type eye development  sequence-specific DNA binding  regulation of DNA methylation  regulation of DNA methylation  negative regulation of keratinocyte differentiation  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  embryonic cranial skeleton morphogenesis  positive regulation of telomerase activity  face development  lung lobe morphogenesis  lung epithelial cell differentiation  epithelial cell morphogenesis involved in placental branching  bicellular tight junction assembly  epithelium migration  
NDEx NetworkGRHL2
Atlas of Cancer Signalling NetworkGRHL2
Wikipedia pathwaysGRHL2
Orthology - Evolution
OrthoDB79977
GeneTree (enSembl)ENSG00000083307
Phylogenetic Trees/Animal Genes : TreeFamGRHL2
HOVERGENQ6ISB3
HOGENOMQ6ISB3
Homologs : HomoloGeneGRHL2
Homology/Alignments : Family Browser (UCSC)GRHL2
Gene fusions - Rearrangements
Fusion : MitelmanGRHL2/CDPF1 [8q22.3/22q13.31]  
Fusion : MitelmanGRHL2/FAM213A [8q22.3/10q23.1]  [t(8;10)(q22;q23)]  
Fusion : MitelmanGRHL2/FAM49A [8q22.3/2p24.2]  [t(2;8)(p24;q22)]  
Fusion : MitelmanGRHL2/KCNRG [8q22.3/13q14.2]  [t(8;13)(q22;q14)]  
Fusion : MitelmanGRHL2/PAGE3 [8q22.3/Xp11.21]  [t(X;8)(p11;q22)]  
Fusion : MitelmanGRHL2/TRAPPC9 [8q22.3/8q24.3]  [t(8;8)(q22;q24)]  
Fusion : MitelmanGRHL2/TRIM13 [8q22.3/13q14.2]  [t(8;13)(q22;q14)]  
Fusion : MitelmanGRHL2/TSPAN14 [8q22.3/10q23.1]  [t(8;10)(q22;q23)]  
Fusion : MitelmanGRHL2/ZFHX4 [8q22.3/8q21.11]  [t(8;8)(q21;q22)]  
Fusion : MitelmanRITA1/GRHL2 [12q24.13/8q22.3]  [t(8;12)(q22;q24)]  
Fusion : MitelmanTMPRSS2/GRHL2 [21q22.3/8q22.3]  [t(8;21)(q22;q22)]  
Fusion: TCGA_MDACCC12orf52 GRHL2 8q22.3 HNSC
Fusion: TCGA_MDACCGRHL2 8q22.3 C10orf58 BRCA
Fusion: TCGA_MDACCGRHL2 8q22.3 C22orf40 HNSC
Fusion: TCGA_MDACCGRHL2 8q22.3 FAM49A 2p24.2 BLCA
Fusion: TCGA_MDACCGRHL2 8q22.3 KCNRG 13q14.2 HNSC
Fusion: TCGA_MDACCGRHL2 8q22.3 PAGE3 Xp11.21 BRCA
Fusion: TCGA_MDACCGRHL2 8q22.3 TRAPPC9 8q24.3 BRCA
Fusion: TCGA_MDACCGRHL2 8q22.3 TRIM13 13q14.2 HNSC
Fusion: TCGA_MDACCGRHL2 8q22.3 TSPAN14 10q23.1 BRCA
Fusion: TCGA_MDACCGRHL2 8q22.3 ZFHX4 8q21.11 BRCA
Fusion: TCGA_MDACCTMPRSS2 21q22.3 GRHL2 8q22.3 PRAD
Tumor Fusion PortalGRHL2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGRHL2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GRHL2
dbVarGRHL2
ClinVarGRHL2
1000_GenomesGRHL2 
Exome Variant ServerGRHL2
ExAC (Exome Aggregation Consortium)ENSG00000083307
GNOMAD BrowserENSG00000083307
Genetic variants : HAPMAP79977
Genomic Variants (DGV)GRHL2 [DGVbeta]
DECIPHERGRHL2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGRHL2 
Mutations
ICGC Data PortalGRHL2 
TCGA Data PortalGRHL2 
Broad Tumor PortalGRHL2
OASIS PortalGRHL2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGRHL2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGRHL2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch GRHL2
DgiDB (Drug Gene Interaction Database)GRHL2
DoCM (Curated mutations)GRHL2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GRHL2 (select a term)
intoGenGRHL2
NCG5 (London)GRHL2
Cancer3DGRHL2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608576    608641    616029   
Orphanet23157    12046   
DisGeNETGRHL2
MedgenGRHL2
Genetic Testing Registry GRHL2
NextProtQ6ISB3 [Medical]
TSGene79977
GENETestsGRHL2
Target ValidationGRHL2
Huge Navigator GRHL2 [HugePedia]
snp3D : Map Gene to Disease79977
BioCentury BCIQGRHL2
ClinGenGRHL2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD79977
Chemical/Pharm GKB GenePA27270
Clinical trialGRHL2
Miscellaneous
canSAR (ICR)GRHL2 (select the gene name)
Probes
Litterature
PubMed43 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGRHL2
EVEXGRHL2
GoPubMedGRHL2
iHOPGRHL2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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