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PARVB (parvin, beta)

Written2010-04Cameron N Johnstone
Cancer Metastasis Laboratory, Research Division, Peter MacCallum Cancer Centre, 2 St Andrew's Place, East Melbourne, 3002, Victoria, Australia

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)CGI-56
Other aliasaffixin
beta-parvin
HGNC (Hugo) PARVB
LocusID (NCBI) 29780
Atlas_Id 46486
Location 22q13.31  [Link to chromosome band 22q13]
Location_base_pair Starts at 44395091 and ends at 44565112 bp from pter ( according to hg19-Feb_2009)  [Mapping PARVB.png]
Local_order PARVB is located telomeric to the SAMM50 gene and centromeric to the PARVG gene at 22q13.31.
Fusion genes
(updated 2016)
CHEK2 (22q12.1) / PARVB (22q13.31)PARVB (22q13.31) / SAMM50 (22q13.31)

DNA/RNA

Note Genethon marker D22S1171 is located at the 5' end of the gene (Mongroo et al., 2004). Genethon marker D22S1171 is located between exon 2 and exon 1A of the PARVB gene.
The PARVA gene is located at 11p15.3.
 
  Figure A. Generation of transcript diversity by alternative promoter usage. Horizontal lines above the gene structure indicate human genomic DNA BAC clones. The NCBI accession numbers of the clones, and clone names (in brackets) are shown. Figure adapted from Mongroo et al., 2004.
Figure B. Human polyA+ RNA Multiple Tissue Northern blot (Origene) probed with full-length PARVB1 cDNA probe radiolabeled to a specific activity of > 5 x 108 cpm / mg (Johnstone C.N., unpublished). The two PARVB mRNA transcripts are indicated. The higher M.W. band most likely corresponds to non-specific hybridization (n/s).
Description PARVB3/CLINT, which encodes the longer Parvin-beta protein isoform is transcribed from promoter 1 and contains two additional 5' exons (exons 1 and 2) not present in PARVB1, and comprises 14 exons in total. PARVB1 encodes the shorter Parvin-beta protein isoform, is transcribed from promoter 1A, and comprises 13 exons in total. Both promoters contain CpG islands that span the transcription start sites. PARVB3/CLINT contains 70 unique N-terminal amino acids not present in the short isoform. (See figure A).
Transcription As with PARVA, human PARVB mRNA expression is highest in heart, followed by skeletal muscle, where it localises to the sarcolemma (Yamaji et al., 2001; Matsuda et al., 2005). Both PARVB mRNA transcripts are essentially ubiquitously expressed (Korenbaum et al., 2001), but with lower expression in gastrointestinal tissues (stomach, small intestine, colon). (See figure B).

Protein

 
  Depiction of functional domains of Parvin-beta(long) and Parvin-beta(short). NLS, nuclear localization sequence; ABS, actin binding sequence; CH, calponin homology. Adapted from Sepulveda and Wu, 2006.
Description The major functional domains of Parvin-beta are two 'atypical' calponin homology (CH) domains, termed CH1 (106 amino acids) and CH2 (107 amino acids). Each CH domain contains two actin binding sequences (ABS), although Parvin-beta has not been shown to bind actin directly (Korenbaum et al., 2001; Sepulveda and Wu, 2006). Parvin-beta physically interacts with Dysferlin and ARHGEF6 (alpha-PIX) through the CH1 domain (Matsuda et al., 2005; Rosenberger et al., 2003) and with ILK and alpha-actinin through the CH2 domain (Yamaji et al., 2001; Yamaji et al., 2004). Parvin-beta was also recently reported to directly interact with AKT (Kimura et al., 2010).
Expression PARVB is essentially ubiquitously expressed.
Localisation Parvin-beta localises to focal adhesions but also to the nucleus, which is most likely due to NLS motifs in the N-terminal region (Mongroo et al., 2004; Johnstone et al., 2008). Parvin-beta is incorporated into focal adhesions as part of the heterotrimeric 'IPP complex'. The ternary complex contains 1 molecule of integrin linked kinase (ILK), 1 Parvin isoform, and 1 PINCH (LIMS) isoform, (Legate et al., 2006). Binding of Parvin-alpha and Parvin-beta to the kinase domain of ILK is mutually exclusive (Zhang et al., 2004). Formation of the IPP complex also dictates total protein levels of each component, as any excess ILK, Parvin, or PINCH not incorporated into IPP is degraded in a proteasome-dependent manner (Fukuda et al., 2003).
Function Parvin-beta participates in focal adhesion dynamics through involvement in the IPP complex. The high expression levels in cardiac and skeletal muscle suggest important function(s) in these organs. In skeletal muscle, it binds dysferlin at the sarcolemma and thus may be involved with membrane repair (Yamaji et al., 2001; Matsuda et al., 2005; Legate et al., 2006). Parvin-beta and Parvin-alpha appear to negatively regulate the expression of each other (Zhang et al., 2004; Johnstone et al., 2008). Parvin-beta may modulate signalling through ILK as overexpression of Parvin-beta reduced AKT (S473) and GSK3beta (S9) phosphorylation in response to EGF stimulation (Mongroo et al., 2004). Parvin-beta was recently reported to directly interact with AKT (Kimura et al., 2010), which may explain its effects on AKT phosphorylation. Parvin-beta interacts with ARHGEF6 (alpha-PIX), an exchange factor for RAC1, thus implicating Parvin-beta in regulation of RAC signalling downstream of integrin engagement (Rosenberger et al., 2003). Finally, Parvin-beta may affect metabolic pathways through promotion of CDK9-mediated phosphorylation and activation of PPARgamma transcriptional activity in the nucleus (Johnstone et al., 2008). Interestingly, Parvb knockout mice were recently generated. Whilst constitutive Parva null mice feature kidney and cardiovascular defects and die between E10.5 and E14.5 (Lange et al., 2009; Montanez et al., 2009), constitutive Parvb null mice are viable (Wickström et al., 2010), although a detailed phenotypic analysis has not yet been described.
Homology Human Parvin-beta is most closely related to Parvin-alpha [75% identity with Parvin-beta(short) and 67% identity with Parvin-beta(long)] and more distantly to Parvin-gamma [41% identity with both Parvin-beta(short) and Parvin-beta(long)].

Mutations

Note No mutations reported to date.
Germinal Germline SNPs are identified in the PARVB gene by direct sequencing of PCR products amplified from cDNA prepared from 16 primary ductal adenocarcinomasand adjacent normal mammary gland from the same patient. Two non-synonymous SNPs were identified, W37R, and E175K (Johnstone et al., manuscript in preparation).
Name
Alleles
Location
Base Position†
Amino Acid Position‡
Amino Acid change
No. of Alleles
A98C
A/C
Intron 1
98**
n/a
n/a
3/8
W37R
T/C
Exon 2
252
37
W>R
3/8
D150D
C/T
Exon 5
593
150
D>D
2/32
E175K
G/A
Exon 6
666
175
E>K
2/32
A223A
C/T
Exon 7
812
223
A>A
2/32
G316G^
C/T
Exon 12
1097
318
G>G
2/32
F354F^
C/T
Exon 13
1205
354
F>F
2/32
† Relative to transcription start site
‡ Relative to translation start site
^ Occur as a haplotype
** Relative to splice site
Somatic No somatic mutations were found in an analysis of 16 breast adenocarcinomas as presented above (Johnstone et al., manuscript in preparation). According to the C.O.S.M.I.C. online database (Forbes et al., 2008), 171 unique cancer samples have been analysed for alterations in the PARVB gene, with no somatic changes found. A breakdown of the samples analysed is given below.
Cancer TypeNo. of SpecimensReference
Breast
11
Sjöblom et al., 2006
Glioma
23
Parsons et al., 2008
Clear Cell Renal
101
Dalgliesh et al., 2010
Colon
12
Sjöblom et al., 2006
Lung (cell lines)
11
N/A
Pancreas (cell lines)
1
N/A
Mesothelioma (cell lines)
1
N/A
Melanoma (cell lines)
6
N/A
Urinary tract (cell lines)
2
N/A
HNSCC (cell lines)
3
N/A

Implicated in

Note
  
Entity Breast cancer
Note Parvin-beta mRNA levels are reduced in primary human ductal adenocarcinoma compared with adjacent normal mammary gland. PARVB mRNA levels are also reduced in MDA-MB-231 and MDA-MB-453 cell lines. Post-transcriptional downregulation of protein expression may also occur in cancer cells such as MCF7 (Mongroo et al., 2004). Ectopic Parvin-beta expression in MDA-MB-231 metastatic breast cancer cells increased adhesion and reduced invasion. Ectopic expression also reduced tumorigenicity of the same cell line in nude mice in vivo. Parvin-beta expression did not affect proliferation of the cells in vitro, but reduced Ki-67 staining was observed in Parvin-beta transfectants in vivo (Johnstone et al., 2008). Parvin-beta overexpression was also reported to promote apoptosis in HeLa cervical cancer cells (Zhang et al., 2004).
Prognosis Association with prognosis has not been studied to date.
  

Bibliography

Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
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The Catalogue of Somatic Mutations in Cancer (COSMIC).
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Curr Protoc Hum Genet. 2008 Apr;Chapter 10:Unit 10.11.
PMID 18428421
 
PINCH-1 is an obligate partner of integrin-linked kinase (ILK) functioning in cell shape modulation, motility, and survival.
Fukuda T, Chen K, Shi X, Wu C.
J Biol Chem. 2003 Dec 19;278(51):51324-33. Epub 2003 Oct 8.
PMID 14551191
 
Parvin-beta inhibits breast cancer tumorigenicity and promotes CDK9-mediated peroxisome proliferator-activated receptor gamma 1 phosphorylation.
Johnstone CN, Mongroo PS, Rich AS, Schupp M, Bowser MJ, Delemos AS, Tobias JW, Liu Y, Hannigan GE, Rustgi AK.
Mol Cell Biol. 2008 Jan;28(2):687-704. Epub 2007 Nov 12.
PMID 17998334
 
Functional molecular imaging of ILK-mediated Akt/PKB signaling cascades and the associated role of beta-parvin.
Kimura M, Murakami T, Kizaka-Kondoh S, Itoh M, Yamamoto K, Hojo Y, Takano M, Kario K, Shimada K, Kobayashi E.
J Cell Sci. 2010 Mar 1;123(Pt 5):747-55.
PMID 20164304
 
Genomic organization and expression profile of the parvin family of focal adhesion proteins in mice and humans.
Korenbaum E, Olski TM, Noegel AA.
Gene. 2001 Nov 14;279(1):69-79.
PMID 11722847
 
Integrin-linked kinase is an adaptor with essential functions during mouse development.
Lange A, Wickstrom SA, Jakobson M, Zent R, Sainio K, Fassler R.
Nature. 2009 Oct 15;461(7266):1002-6.
PMID 19829382
 
ILK, PINCH and parvin: the tIPP of integrin signalling.
Legate KR, Montanez E, Kudlacek O, Fassler R.
Nat Rev Mol Cell Biol. 2006 Jan;7(1):20-31. (REVIEW)
PMID 16493410
 
Dysferlin interacts with affixin (beta-parvin) at the sarcolemma.
Matsuda C, Kameyama K, Tagawa K, Ogawa M, Suzuki A, Yamaji S, Okamoto H, Nishino I, Hayashi YK.
J Neuropathol Exp Neurol. 2005 Apr;64(4):334-40.
PMID 15835269
 
Beta-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer.
Mongroo PS, Johnstone CN, Naruszewicz I, Leung-Hagesteijn C, Sung RK, Carnio L, Rustgi AK, Hannigan GE.
Oncogene. 2004 Nov 25;23(55):8959-70.
PMID 15467740
 
Alpha-parvin controls vascular mural cell recruitment to vessel wall by regulating RhoA/ROCK signalling.
Montanez E, Wickstrom SA, Altstatter J, Chu H, Fassler R.
EMBO J. 2009 Oct 21;28(20):3132-44. Epub 2009 Oct 1.
PMID 19798050
 
An integrated genomic analysis of human glioblastoma multiforme.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW.
Science. 2008 Sep 26;321(5897):1807-12. Epub 2008 Sep 4.
PMID 18772396
 
Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling.
Rosenberger G, Jantke I, Gal A, Kutsche K.
Hum Mol Genet. 2003 Jan 15;12(2):155-67.
PMID 12499396
 
The parvins.
Sepulveda JL, Wu C.
Cell Mol Life Sci. 2006 Jan;63(1):25-35. (REVIEW)
PMID 16314921
 
The consensus coding sequences of human breast and colorectal cancers.
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE.
Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7.
PMID 16959974
 
The ILK/PINCH/parvin complex: the kinase is dead, long live the pseudokinase!
Wickstrom SA, Lange A, Montanez E, Fassler R.
EMBO J. 2010 Jan 20;29(2):281-91. Epub 2009 Dec 24. (REVIEW)
PMID 20033063
 
Affixin interacts with alpha-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell-substrate interaction.
Yamaji S, Suzuki A, Kanamori H, Mishima W, Yoshimi R, Takasaki H, Takabayashi M, Fujimaki K, Fujisawa S, Ohno S, Ishigatsubo Y.
J Cell Biol. 2004 May 24;165(4):539-51.
PMID 15159419
 
Distinct roles of two structurally closely related focal adhesion proteins, alpha-parvins and beta-parvins, in regulation of cell morphology and survival.
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Citation

This paper should be referenced as such :
Johnstone, CN
PARVB (parvin, beta)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(1):34-38.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PARVBID46486ch22q13.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  del(13q) in chronic lymphocytic leukemia


External links

Nomenclature
HGNC (Hugo)PARVB   14653
Cards
AtlasPARVBID46486ch22q13
Entrez_Gene (NCBI)PARVB  29780  parvin beta
AliasesCGI-56
GeneCards (Weizmann)PARVB
Ensembl hg19 (Hinxton)ENSG00000188677 [Gene_View]  chr22:44395091-44565112 [Contig_View]  PARVB [Vega]
Ensembl hg38 (Hinxton)ENSG00000188677 [Gene_View]  chr22:44395091-44565112 [Contig_View]  PARVB [Vega]
ICGC DataPortalENSG00000188677
TCGA cBioPortalPARVB
AceView (NCBI)PARVB
Genatlas (Paris)PARVB
WikiGenes29780
SOURCE (Princeton)PARVB
Genetics Home Reference (NIH)PARVB
Genomic and cartography
GoldenPath hg19 (UCSC)PARVB  -     chr22:44395091-44565112 +  22q13.2-q13.33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PARVB  -     22q13.2-q13.33   [Description]    (hg38-Dec_2013)
EnsemblPARVB - 22q13.2-q13.33 [CytoView hg19]  PARVB - 22q13.2-q13.33 [CytoView hg38]
Mapping of homologs : NCBIPARVB [Mapview hg19]  PARVB [Mapview hg38]
OMIM608121   
Gene and transcription
Genbank (Entrez)AB048276 AF151814 AF237769 AF303887 AK308443
RefSeq transcript (Entrez)NM_001003828 NM_001243385 NM_001243386 NM_013327
RefSeq genomic (Entrez)NC_000022 NC_018933 NG_029743 NT_011520 NW_004929430
Consensus coding sequences : CCDS (NCBI)PARVB
Cluster EST : UnigeneHs.475074 [ NCBI ]
CGAP (NCI)Hs.475074
Alternative Splicing GalleryENSG00000188677
Gene ExpressionPARVB [ NCBI-GEO ]   PARVB [ EBI - ARRAY_EXPRESS ]   PARVB [ SEEK ]   PARVB [ MEM ]
Gene Expression Viewer (FireBrowse)PARVB [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)29780
GTEX Portal (Tissue expression)PARVB
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9HBI1   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9HBI1  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9HBI1
Splice isoforms : SwissVarQ9HBI1
PhosPhoSitePlusQ9HBI1
Domaine pattern : Prosite (Expaxy)CH (PS50021)   
Domains : Interpro (EBI)CH-domain    Parvin   
Domain families : Pfam (Sanger)CH (PF00307)   
Domain families : Pfam (NCBI)pfam00307   
Domain families : Smart (EMBL)CH (SM00033)  
Conserved Domain (NCBI)PARVB
DMDM Disease mutations29780
Blocks (Seattle)PARVB
PDB (SRS)4EDL    4EDM    4EDN   
PDB (PDBSum)4EDL    4EDM    4EDN   
PDB (IMB)4EDL    4EDM    4EDN   
PDB (RSDB)4EDL    4EDM    4EDN   
Structural Biology KnowledgeBase4EDL    4EDM    4EDN   
SCOP (Structural Classification of Proteins)4EDL    4EDM    4EDN   
CATH (Classification of proteins structures)4EDL    4EDM    4EDN   
SuperfamilyQ9HBI1
Human Protein AtlasENSG00000188677
Peptide AtlasQ9HBI1
HPRD16284
IPIIPI00043083   IPI00382605   IPI00879834   IPI00877647   IPI00880124   
Protein Interaction databases
DIP (DOE-UCLA)Q9HBI1
IntAct (EBI)Q9HBI1
FunCoupENSG00000188677
BioGRIDPARVB
STRING (EMBL)PARVB
ZODIACPARVB
Ontologies - Pathways
QuickGOQ9HBI1
Ontology : AmiGOactin binding  protein binding  cytosol  cytoskeleton  plasma membrane  focal adhesion  cell adhesion  Z disc  lamellipodium  cell projection assembly  lamellipodium assembly  actin cytoskeleton reorganization  establishment or maintenance of cell polarity regulating cell shape  
Ontology : EGO-EBIactin binding  protein binding  cytosol  cytoskeleton  plasma membrane  focal adhesion  cell adhesion  Z disc  lamellipodium  cell projection assembly  lamellipodium assembly  actin cytoskeleton reorganization  establishment or maintenance of cell polarity regulating cell shape  
Pathways : KEGGFocal adhesion   
REACTOMEQ9HBI1 [protein]
REACTOME Pathways446353 [pathway]   446388 [pathway]   
NDEx NetworkPARVB
Atlas of Cancer Signalling NetworkPARVB
Wikipedia pathwaysPARVB
Orthology - Evolution
OrthoDB29780
GeneTree (enSembl)ENSG00000188677
Phylogenetic Trees/Animal Genes : TreeFamPARVB
HOVERGENQ9HBI1
HOGENOMQ9HBI1
Homologs : HomoloGenePARVB
Homology/Alignments : Family Browser (UCSC)PARVB
Gene fusions - Rearrangements
Fusion : MitelmanCHEK2/PARVB [22q12.1/22q13.31]  [inv(22)(q12q13)]  
Fusion : MitelmanPARVB/SAMM50 [22q13.31/22q13.31]  [t(22;22)(q13;q13)]  
Fusion: TCGAPARVB 22q13.31 SAMM50 22q13.31 OV
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPARVB [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PARVB
dbVarPARVB
ClinVarPARVB
1000_GenomesPARVB 
Exome Variant ServerPARVB
ExAC (Exome Aggregation Consortium)PARVB (select the gene name)
Genetic variants : HAPMAP29780
Genomic Variants (DGV)PARVB [DGVbeta]
DECIPHER (Syndromes)22:44395091-44565112  ENSG00000188677
CONAN: Copy Number AnalysisPARVB 
Mutations
ICGC Data PortalPARVB 
TCGA Data PortalPARVB 
Broad Tumor PortalPARVB
OASIS PortalPARVB [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPARVB  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPARVB
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 PARVB
DgiDB (Drug Gene Interaction Database)PARVB
DoCM (Curated mutations)PARVB (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PARVB (select a term)
intoGenPARVB
NCG5 (London)PARVB
Cancer3DPARVB(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608121   
Orphanet
MedgenPARVB
Genetic Testing Registry PARVB
NextProtQ9HBI1 [Medical]
TSGene29780
GENETestsPARVB
Huge Navigator PARVB [HugePedia]
snp3D : Map Gene to Disease29780
BioCentury BCIQPARVB
ClinGenPARVB
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD29780
Chemical/Pharm GKB GenePA32951
Clinical trialPARVB
Miscellaneous
canSAR (ICR)PARVB (select the gene name)
Probes
Litterature
PubMed47 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePARVB
EVEXPARVB
GoPubMedPARVB
iHOPPARVB
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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