PARVB (parvin, beta)

2010-04-01   Cameron N Johnstone 

Cancer Metastasis Laboratory, Research Division, Peter MacCallum Cancer Centre, 2 St Andrews Place, East Melbourne, 3002, Victoria, Australia

Identity

HGNC
LOCATION
22q13.31
LOCUSID
ALIAS
CGI-56
FUSION GENES

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.
Atlas Image
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 5 x 108 cpm / mg (Johnstone C.N., unpublished).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).

Proteins

Atlas Image
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).
NameAllelesLocationBase Position†Amino Acid Position‡Amino Acid changeNo. of Alleles
A98CA/CIntron 198**n/an/a3/8
W37RT/CExon 225237W>R3/8
D150DC/TExon 5593150D>D2/32
E175KG/AExon 6666175E>K2/32
A223AC/TExon 7812223A>A2/32
G316G^C/TExon 121097318G>G2/32
F354F^C/TExon 131205354F>F2/32
† 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
Breast11Sjöblom et al., 2006
Glioma23Parsons et al., 2008
Clear Cell Renal101Dalgliesh et al., 2010
Colon12Sjöblom et al., 2006
Lung (cell lines)11N/A
Pancreas (cell lines)1N/A
Mesothelioma (cell lines)1N/A
Melanoma (cell lines)6N/A
Urinary tract (cell lines)2N/A
HNSCC (cell lines)3N/A

Implicated in

Entity name
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

Pubmed IDLast YearTitleAuthors
200542972010Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.Dalgliesh GL et al
184284212008The Catalogue of Somatic Mutations in Cancer (COSMIC).Forbes SA et al
145511912003PINCH-1 is an obligate partner of integrin-linked kinase (ILK) functioning in cell shape modulation, motility, and survival.Fukuda T et al
179983342008Parvin-beta inhibits breast cancer tumorigenicity and promotes CDK9-mediated peroxisome proliferator-activated receptor gamma 1 phosphorylation.Johnstone CN et al
201643042010Functional molecular imaging of ILK-mediated Akt/PKB signaling cascades and the associated role of beta-parvin.Kimura M et al
117228472001Genomic organization and expression profile of the parvin family of focal adhesion proteins in mice and humans.Korenbaum E et al
198293822009Integrin-linked kinase is an adaptor with essential functions during mouse development.Lange A et al
164934102006ILK, PINCH and parvin: the tIPP of integrin signalling.Legate KR et al
158352692005Dysferlin interacts with affixin (beta-parvin) at the sarcolemma.Matsuda C et al
154677402004Beta-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer.Mongroo PS et al
197980502009Alpha-parvin controls vascular mural cell recruitment to vessel wall by regulating RhoA/ROCK signalling.Montanez E et al
187723962008An integrated genomic analysis of human glioblastoma multiforme.Parsons DW et al
124993962003Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling.Rosenberger G et al
163149212006The parvins.Sepulveda JL et al
169599742006The consensus coding sequences of human breast and colorectal cancers.Sjöblom T et al
200330632010The ILK/PINCH/parvin complex: the kinase is dead, long live the pseudokinase!Wickström SA et al
151594192004Affixin interacts with alpha-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell-substrate interaction.Yamaji S et al
152842462004Distinct roles of two structurally closely related focal adhesion proteins, alpha-parvins and beta-parvins, in regulation of cell morphology and survival.Zhang Y et al

Other Information

Locus ID:

NCBI: 29780
MIM: 608121
HGNC: 14653
Ensembl: ENSG00000188677

Variants:

dbSNP: 29780
ClinVar: 29780
TCGA: ENSG00000188677
COSMIC: PARVB

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000188677ENST00000338758Q9HBI1
ENSG00000188677ENST00000404989Q9HBI1
ENSG00000188677ENST00000406477Q9HBI1
ENSG00000188677ENST00000444029B0QYP8
ENSG00000188677ENST00000619710A0A087WZB5

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Focal adhesionKEGGko04510
Focal adhesionKEGGhsa04510
Cell-Cell communicationREACTOMER-HSA-1500931
Cell junction organizationREACTOMER-HSA-446728
Cell-extracellular matrix interactionsREACTOMER-HSA-446353
Regulation of cytoskeletal remodeling and cell spreading by IPP complex componentsREACTOMER-HSA-446388

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203454892010The Legionella pneumophila F-box protein Lpp2082 (AnkB) modulates ubiquitination of the host protein parvin B and promotes intracellular replication.74
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
235359112013Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan.58
152842462004Distinct roles of two structurally closely related focal adhesion proteins, alpha-parvins and beta-parvins, in regulation of cell morphology and survival.31
158352692005Dysferlin interacts with affixin (beta-parvin) at the sarcolemma.25
151594192004Affixin interacts with alpha-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell-substrate interaction.22
154677402004Beta-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer.19
150057072004The first CH domain of affixin activates Cdc42 and Rac1 through alphaPIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor.18
228693802012Structural basis for paxillin binding and focal adhesion targeting of β-parvin.17
179983342008Parvin-beta inhibits breast cancer tumorigenicity and promotes CDK9-mediated peroxisome proliferator-activated receptor gamma 1 phosphorylation.14

Citation

Cameron N Johnstone

PARVB (parvin, beta)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: http://atlasgeneticsoncology.org/gene/46486/parvb