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Protein

Grainyhead-like protein 2 homolog

Gene

GRHL2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcription factor playing an important role in primary neurulation and in epithelial development (PubMed:25152456). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (By similarity). During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Regulates epithelial morphogenesis acting as a target gene-associated transcriptional activator of apical junctional complex components. Up-regulates of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at tight junctions (By similarity). Comprises an essential component of the transcriptional machinery that establishes appropriate expression levels of CLDN4 and CDH1 in different types of epithelia. Exhibits functional redundancy with GRHL3 in epidermal morphogenetic events and epidermal wound repair (By similarity). In lung, forms a regulatory loop with NKX2-1 that coordinates lung epithelial cell morphogenesis and differentiation (By similarity). In keratinocytes, plays a role in telomerase activation during cellular proliferation, regulates TERT expression by binding to TERT promoter region and inhibiting DNA methylation at the 5'-CpG island, possibly by interfering with DNMT1 enzyme activity (PubMed:19015635, PubMed:20938050). In addition, impairs keratinocyte differentiation and epidermal function by inhibiting the expression of genes clustered at the epidermal differentiation complex (EDC) as well as GRHL1 and GRHL3 through epigenetic mechanisms (PubMed:23254293).By similarity1 Publication5 Publications

GO - Molecular functioni

GO - Biological processi

  • bicellular tight junction assembly Source: UniProtKB
  • brain development Source: GO_Central
  • camera-type eye development Source: Ensembl
  • cardiac ventricle morphogenesis Source: Ensembl
  • cell adhesion Source: UniProtKB
  • cell junction assembly Source: UniProtKB
  • cell proliferation Source: UniProtKB
  • embryonic cranial skeleton morphogenesis Source: Ensembl
  • embryonic digit morphogenesis Source: Ensembl
  • epidermis development Source: UniProtKB
  • epithelial cell morphogenesis Source: UniProtKB
  • epithelial cell morphogenesis involved in placental branching Source: Ensembl
  • epithelium migration Source: UniProtKB
  • face development Source: Ensembl
  • lung epithelial cell differentiation Source: UniProtKB
  • lung lobe morphogenesis Source: Ensembl
  • multicellular organism growth Source: Ensembl
  • negative regulation of keratinocyte differentiation Source: UniProtKB
  • neural tube closure Source: UniProtKB
  • neural tube development Source: GO_Central
  • positive regulation of telomerase activity Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • regulation of DNA methylation Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Grainyhead-like protein 2 homolog
Alternative name(s):
Brother of mammalian grainyhead
Transcription factor CP2-like 3
Gene namesi
Name:GRHL2
Synonyms:BOM, TFCP2L3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

HGNCiHGNC:2799. GRHL2.

Subcellular locationi

GO - Cellular componenti

  • cell-cell junction Source: UniProtKB
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
  • plasma membrane Source: HPA
Complete GO annotation...

Keywords - Cellular componenti

Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Deafness, autosomal dominant, 28 (DFNA28)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA28 is characterized by mild to moderate hearing loss across most frequencies that progresses to severe loss in the higher frequencies by the fifth decade.
See also OMIM:608641
Ectodermal dysplasia/short stature syndrome (ECTDS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive ectodermal dysplasia syndrome characterized by nail dystrophy and/or loss, oral mucosa and/or tongue pigmentation, abnormal dentition, keratoderma affecting the margins of the palms and soles, focal hyperkeratosis of the dorsal aspects of the hands and feet, and short stature.
See also OMIM:616029
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071989398Y → H in ECTDS. 1 PublicationCorresponds to variant rs587777737dbSNPEnsembl.1
Natural variantiVAR_071990482I → K in ECTDS; reduced expression; altered cell morphology; impaired tight junctions; adhesion defects; cytoplasmic translocation. 1 PublicationCorresponds to variant rs587777738dbSNPEnsembl.1

Keywords - Diseasei

Deafness, Disease mutation, Dwarfism, Ectodermal dysplasia, Non-syndromic deafness

Organism-specific databases

DisGeNETi79977.
MalaCardsiGRHL2.
MIMi608641. phenotype.
616029. phenotype.
OpenTargetsiENSG00000083307.
Orphaneti90635. Autosomal dominant non-syndromic sensorineural deafness type DFNA.
PharmGKBiPA27270.

Polymorphism and mutation databases

BioMutaiGRHL2.
DMDMi74736618.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002279941 – 625Grainyhead-like protein 2 homologAdd BLAST625

Proteomic databases

EPDiQ6ISB3.
MaxQBiQ6ISB3.
PaxDbiQ6ISB3.
PeptideAtlasiQ6ISB3.
PRIDEiQ6ISB3.

PTM databases

iPTMnetiQ6ISB3.
PhosphoSitePlusiQ6ISB3.

Expressioni

Tissue specificityi

Expressed in keratinocytes (at protein level). Highly expressed in placenta, prostate, brain and kidney. Lower-level expression in a variety of epithelial tissues such as thymus, lung, salivary gland, mammary gland and digestive tract. Expressed in the cochlear.4 Publications

Inductioni

Expressed in proliferating cells, the expression decreases during senescence. In keratinocytes, expression levels decrease upon calcium exposure.2 Publications

Gene expression databases

BgeeiENSG00000083307.
CleanExiHS_GRHL2.
GenevisibleiQ6ISB3. HS.

Organism-specific databases

HPAiHPA004820.
HPA062839.

Interactioni

Subunit structurei

Homodimer, also forms heterodimers with GRHL1 or GRHL3.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
LMO4P619685EBI-10219092,EBI-2798728

Protein-protein interaction databases

BioGridi123042. 4 interactors.
IntActiQ6ISB3. 3 interactors.
STRINGi9606.ENSP00000251808.

Structurei

3D structure databases

ProteinModelPortaliQ6ISB3.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 93Transcription activationBy similarityAdd BLAST93

Sequence similaritiesi

Belongs to the grh/CP2 family. Grainyhead subfamily.Curated

Phylogenomic databases

eggNOGiKOG4091. Eukaryota.
ENOG410XNZ6. LUCA.
GeneTreeiENSGT00760000119235.
HOGENOMiHOG000220859.
HOVERGENiHBG054154.
InParanoidiQ6ISB3.
KOiK09275.
OMAiKITKLYK.
OrthoDBiEOG091G03ME.
PhylomeDBiQ6ISB3.
TreeFamiTF314132.

Family and domain databases

InterProiIPR007604. CP2.
[Graphical view]
PfamiPF04516. CP2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q6ISB3-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSQESDNNKR LVALVPMPSD PPFNTRRAYT SEDEAWKSYL ENPLTAATKA
60 70 80 90 100
MMSINGDEDS AAALGLLYDY YKVPRDKRLL SVSKASDSQE DQEKRNCLGT
110 120 130 140 150
SEAQSNLSGG ENRVQVLKTV PVNLSLNQDH LENSKREQYS ISFPESSAII
160 170 180 190 200
PVSGITVVKA EDFTPVFMAP PVHYPRGDGE EQRVVIFEQT QYDVPSLATH
210 220 230 240 250
SAYLKDDQRS TPDSTYSESF KDAATEKFRS ASVGAEEYMY DQTSSGTFQY
260 270 280 290 300
TLEATKSLRQ KQGEGPMTYL NKGQFYAITL SETGDNKCFR HPISKVRSVV
310 320 330 340 350
MVVFSEDKNR DEQLKYWKYW HSRQHTAKQR VLDIADYKES FNTIGNIEEI
360 370 380 390 400
AYNAVSFTWD VNEEAKIFIT VNCLSTDFSS QKGVKGLPLM IQIDTYSYNN
410 420 430 440 450
RSNKPIHRAY CQIKVFCDKG AERKIRDEER KQNRKKGKGQ ASQTQCNSSS
460 470 480 490 500
DGKLAAIPLQ KKSDITYFKT MPDLHSQPVL FIPDVHFANL QRTGQVYYNT
510 520 530 540 550
DDEREGGSVL VKRMFRPMEE EFGPVPSKQM KEEGTKRVLL YVRKETDDVF
560 570 580 590 600
DALMLKSPTV KGLMEAISEK YGLPVEKIAK LYKKSKKGIL VNMDDNIIEH
610 620
YSNEDTFILN MESMVEGFKV TLMEI
Length:625
Mass (Da):71,105
Last modified:July 5, 2004 - v1
Checksum:i147CF33798248BB6
GO
Isoform 2 (identifier: Q6ISB3-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-16: Missing.

Show »
Length:609
Mass (Da):69,322
Checksum:iE43F12B929E3473D
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti53S → I in BAB14699 (PubMed:14702039).Curated1
Sequence conflicti430R → Q in BAB14699 (PubMed:14702039).Curated1
Sequence conflicti436K → N in BAB14699 (PubMed:14702039).Curated1
Sequence conflicti561K → M in BAB14699 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071989398Y → H in ECTDS. 1 PublicationCorresponds to variant rs587777737dbSNPEnsembl.1
Natural variantiVAR_049293415V → I.Corresponds to variant rs3779617dbSNPEnsembl.1
Natural variantiVAR_071990482I → K in ECTDS; reduced expression; altered cell morphology; impaired tight junctions; adhesion defects; cytoplasmic translocation. 1 PublicationCorresponds to variant rs587777738dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0176421 – 16Missing in isoform 2. 1 PublicationAdd BLAST16

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK023844 mRNA. Translation: BAB14699.1.
CH471060 Genomic DNA. Translation: EAW91834.1.
BC069618 mRNA. Translation: AAH69618.1.
BC069633 mRNA. Translation: AAH69633.1.
BC069638 mRNA. Translation: AAH69638.1.
BC129822 mRNA. Translation: AAI29823.1.
BC129823 mRNA. Translation: AAI29824.1.
CCDSiCCDS34931.1. [Q6ISB3-1]
CCDS83312.1. [Q6ISB3-2]
RefSeqiNP_001317522.1. NM_001330593.1.
NP_079191.2. NM_024915.3. [Q6ISB3-1]
XP_011515608.1. XM_011517306.2. [Q6ISB3-2]
UniGeneiHs.661088.
Hs.690766.

Genome annotation databases

EnsembliENST00000251808; ENSP00000251808; ENSG00000083307. [Q6ISB3-1]
ENST00000395927; ENSP00000379260; ENSG00000083307. [Q6ISB3-2]
GeneIDi79977.
KEGGihsa:79977.
UCSCiuc010mbu.4. human. [Q6ISB3-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK023844 mRNA. Translation: BAB14699.1.
CH471060 Genomic DNA. Translation: EAW91834.1.
BC069618 mRNA. Translation: AAH69618.1.
BC069633 mRNA. Translation: AAH69633.1.
BC069638 mRNA. Translation: AAH69638.1.
BC129822 mRNA. Translation: AAI29823.1.
BC129823 mRNA. Translation: AAI29824.1.
CCDSiCCDS34931.1. [Q6ISB3-1]
CCDS83312.1. [Q6ISB3-2]
RefSeqiNP_001317522.1. NM_001330593.1.
NP_079191.2. NM_024915.3. [Q6ISB3-1]
XP_011515608.1. XM_011517306.2. [Q6ISB3-2]
UniGeneiHs.661088.
Hs.690766.

3D structure databases

ProteinModelPortaliQ6ISB3.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi123042. 4 interactors.
IntActiQ6ISB3. 3 interactors.
STRINGi9606.ENSP00000251808.

PTM databases

iPTMnetiQ6ISB3.
PhosphoSitePlusiQ6ISB3.

Polymorphism and mutation databases

BioMutaiGRHL2.
DMDMi74736618.

Proteomic databases

EPDiQ6ISB3.
MaxQBiQ6ISB3.
PaxDbiQ6ISB3.
PeptideAtlasiQ6ISB3.
PRIDEiQ6ISB3.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000251808; ENSP00000251808; ENSG00000083307. [Q6ISB3-1]
ENST00000395927; ENSP00000379260; ENSG00000083307. [Q6ISB3-2]
GeneIDi79977.
KEGGihsa:79977.
UCSCiuc010mbu.4. human. [Q6ISB3-1]

Organism-specific databases

CTDi79977.
DisGeNETi79977.
GeneCardsiGRHL2.
GeneReviewsiGRHL2.
HGNCiHGNC:2799. GRHL2.
HPAiHPA004820.
HPA062839.
MalaCardsiGRHL2.
MIMi608576. gene.
608641. phenotype.
616029. phenotype.
neXtProtiNX_Q6ISB3.
OpenTargetsiENSG00000083307.
Orphaneti90635. Autosomal dominant non-syndromic sensorineural deafness type DFNA.
PharmGKBiPA27270.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG4091. Eukaryota.
ENOG410XNZ6. LUCA.
GeneTreeiENSGT00760000119235.
HOGENOMiHOG000220859.
HOVERGENiHBG054154.
InParanoidiQ6ISB3.
KOiK09275.
OMAiKITKLYK.
OrthoDBiEOG091G03ME.
PhylomeDBiQ6ISB3.
TreeFamiTF314132.

Miscellaneous databases

ChiTaRSiGRHL2. human.
GenomeRNAii79977.
PROiQ6ISB3.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000083307.
CleanExiHS_GRHL2.
GenevisibleiQ6ISB3. HS.

Family and domain databases

InterProiIPR007604. CP2.
[Graphical view]
PfamiPF04516. CP2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGRHL2_HUMAN
AccessioniPrimary (citable) accession number: Q6ISB3
Secondary accession number(s): A1L303, Q6NT03, Q9H8B8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 21, 2006
Last sequence update: July 5, 2004
Last modified: November 30, 2016
This is version 111 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

GRHL genes (GRHL1, GRHL2 and GRHL3) show a paradoxal lack of redundancy despite their extensive sequence identity in the DNA-binding and protein dimerization domains and the fact that the core consensus DNA binding sites are identical. They have related but remarkably different functions during embryogenesis because of their differential spatiotemporal expression patterns during development.By similarity

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 8
    Human chromosome 8: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.