Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

PARVB (parvin, beta) Cameron N Johnstone Cancer Metastasis Laboratory, Research Division, Peter MacCallum Cancer Centre, 2 St Andrew's Place, East Melbourne, 3002, Victoria, Australia (CNJ)

Published in Atlas Database: April 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/PARVBID46486ch22q13.html DOI: 10.4267/2042/44936 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: CGI-56, affixin, beta-parvin Note HGNC (Hugo): PARVB Genethon marker D22S1171 is located at the 5' end of Location: 22q13.31 the gene (Mongroo et al., 2004). Genethon marker Local order: PARVB is located telomeric to the D22S1171 is located between exon 2 and exon 1A of SAMM50 gene and centromeric to the PARVG gene the PARVB gene. at 22q13.31. 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.

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) 34 PARVB (parvin, beta) Johnstone CN

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 5 x 108 cpm / mg (Johnstone C.N., unpublished).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 (ABS), although Parvin-beta has not been shown to bind actin directly (Korenbaum et al., 2001; Sepulveda PARVB3/CLINT, which encodes the longer Parvin- and Wu, 2006). Parvin-beta physically interacts with beta protein isoform is transcribed from promoter 1 and Dysferlin and ARHGEF6 (alpha-PIX) through the CH1 contains two additional 5' exons (exons 1 and 2) not domain (Matsuda et al., 2005; Rosenberger et al., 2003) present in PARVB1, and comprises 14 exons in total. and with ILK and alpha-actinin through the CH2 PARVB1 encodes the shorter Parvin-beta protein domain (Yamaji et al., 2001; Yamaji et al., 2004). isoform, is transcribed from promoter 1A, and Parvin-beta was also recently reported to directly comprises 13 exons in total. Both promoters contain interact with AKT (Kimura et al., 2010). CpG islands that span the transcription start sites. PARVB3/CLINT contains 70 unique N-terminal amino Expression acids not present in the short isoform. (See figure A). PARVB is essentially ubiquitously expressed. Transcription Localisation As with PARVA, human PARVB mRNA expression is Parvin-beta localises to focal adhesions but also to the highest in heart, followed by skeletal muscle, where it nucleus, which is most likely due to NLS motifs in the localises to the sarcolemma (Yamaji et al., 2001; N-terminal region (Mongroo et al., 2004; Johnstone et Matsuda et al., 2005). Both PARVB mRNA transcripts al., 2008). Parvin-beta is incorporated into focal are essentially ubiquitously expressed (Korenbaum et adhesions as part of the heterotrimeric 'IPP complex'. al., 2001), but with lower expression in gastrointestinal The ternary complex contains 1 molecule of integrin tissues (stomach, small intestine, colon). (See figure B). linked kinase (ILK), 1 Parvin isoform, and 1 PINCH (LIMS) isoform, (Legate et al., 2006). Binding of Protein Parvin-alpha and Parvin-beta to the kinase domain of ILK is mutually exclusive (Zhang et al., 2004). Description Formation of the IPP complex also dictates total protein The major functional domains of Parvin-beta are two levels of each component, as any excess ILK, Parvin, 'atypical' calponin homology (CH) domains, termed or PINCH not incorporated into IPP is degraded in a CH1 (106 amino acids) and CH2 (107 amino acids). proteasome-dependent manner (Fukuda et al., 2003). Each CH domain contains two actin binding sequences

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1) 35 PARVB (parvin, beta) Johnstone CN

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.

Function Homology Parvin-beta participates in focal adhesion dynamics Human Parvin-beta is most closely related to Parvin- through involvement in the IPP complex. The high alpha [75% identity with Parvin-beta(short) and 67% expression levels in cardiac and skeletal muscle suggest identity with Parvin-beta(long)] and more distantly to important function(s) in these organs. In skeletal Parvin-gamma [41% identity with both Parvin- muscle, it binds dysferlin at the sarcolemma and thus beta(short) and Parvin-beta(long)]. may be involved with membrane repair (Yamaji et al., 2001; Matsuda et al., 2005; Legate et al., 2006). Parvin- Mutations beta and Parvin-alpha appear to negatively regulate the expression of each other (Zhang et al., 2004; Johnstone Note et al., 2008). Parvin-beta may modulate signalling No mutations reported to date. through ILK as overexpression of Parvin-beta reduced Germinal AKT (S473) and GSK3beta (S9) phosphorylation in Germline SNPs are identified in the PARVB gene by response to EGF stimulation (Mongroo et al., 2004). direct sequencing of PCR products amplified from Parvin-beta was recently reported to directly interact cDNA prepared from 16 primary ductal with AKT (Kimura et al., 2010), which may explain its adenocarcinomasand adjacent normal mammary gland effects on AKT phosphorylation. Parvin-beta interacts from the same patient. Two non-synonymous SNPs with ARHGEF6 (alpha-PIX), an exchange factor for were identified, W37R, and E175K (Johnstone et al., RAC1, thus implicating Parvin-beta in regulation of manuscript in preparation). RAC signalling downstream of integrin engagement (Rosenberger et al., 2003). Finally, Parvin-beta may Somatic affect metabolic pathways through promotion of No somatic mutations were found in an analysis of 16 CDK9-mediated phosphorylation and activation of breast adenocarcinomas as presented above (Johnstone PPARgamma transcriptional activity in the nucleus et al., manuscript in preparation). According to the (Johnstone et al., 2008). Interestingly, Parvb knockout C.O.S.M.I.C. online database (Forbes et al., 2008), 171 mice were recently generated. Whilst constitutive Parva unique cancer samples have been analysed for null mice feature kidney and cardiovascular defects and alterations in the PARVB gene, with no somatic die between E10.5 and E14.5 (Lange et al., 2009; changes found. A breakdown of the samples analysed Montanez et al., 2009), constitutive Parvb null mice are is given below. viable (Wickström et al., 2010), although a detailed phenotypic analysis has not yet been described.

Amino Acid Amino Acid Name Alleles Location Base Position† No. of Alleles Position‡ change 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

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** Relative to splice site

Cancer Type No. of Specimens Reference 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

involvement of alphaPIX in integrin-mediated signaling. Hum Implicated in Mol Genet. 2003 Jan 15;12(2):155-67 Breast cancer Mongroo PS, Johnstone CN, Naruszewicz I, Leung-Hagesteijn C, Sung RK, Carnio L, Rustgi AK, Hannigan GE. Beta-parvin Note inhibits integrin-linked kinase signaling and is downregulated in Parvin-beta mRNA levels are reduced in primary breast cancer. Oncogene. 2004 Nov 25;23(55):8959-70 human ductal adenocarcinoma compared with adjacent Yamaji S, Suzuki A, Kanamori H, Mishima W, Yoshimi R, et al. normal mammary gland. PARVB mRNA levels are Affixin interacts with alpha-actinin and mediates integrin also reduced in MDA-MB-231 and MDA-MB-453 cell signaling for reorganization of F-actin induced by initial cell- substrate interaction. J Cell Biol. 2004 May 24;165(4):539-51 lines. Post-transcriptional downregulation of protein expression may also occur in cancer cells such as Zhang Y, Chen K, Tu Y, Wu C. Distinct roles of two structurally closely related focal adhesion proteins, alpha-parvins and MCF7 (Mongroo et al., 2004). Ectopic Parvin-beta beta-parvins, in regulation of cell morphology and survival. J expression in MDA-MB-231 metastatic breast cancer Biol Chem. 2004 Oct 1;279(40):41695-705 cells increased adhesion and reduced invasion. Ectopic Matsuda C, Kameyama K, Tagawa K, Ogawa M, Suzuki A, et expression also reduced tumorigenicity of the same cell al. Dysferlin interacts with affixin (beta-parvin) at the line in nude mice in vivo. Parvin-beta expression did sarcolemma. J Neuropathol Exp Neurol. 2005 Apr;64(4):334- not affect proliferation of the cells in vitro, but reduced 40 Ki-67 staining was observed in Parvin-beta Legate KR, Montañez E, Kudlacek O, Fässler R. ILK, PINCH transfectants in vivo (Johnstone et al., 2008). Parvin- and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell beta overexpression was also reported to promote Biol. 2006 Jan;7(1):20-31 apoptosis in HeLa cervical cancer cells (Zhang et al., Sepulveda JL, Wu C. The parvins. Cell Mol Life Sci. 2006 2004). Jan;63(1):25-35 Prognosis Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, et al. The Association with prognosis has not been studied to consensus coding sequences of human breast and colorectal date. cancers. Science. 2006 Oct 13;314(5797):268-74 Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, References Clements J, Menzies A, Teague JW, Futreal PA, Stratton MR. The Catalogue of Somatic Mutations in Cancer (COSMIC). Korenbaum E, Olski TM, Noegel AA. Genomic organization Curr Protoc Hum Genet. 2008 Apr;Chapter 10:Unit 10.11 and expression profile of the parvin family of focal adhesion proteins in mice and humans. Gene. 2001 Nov 14;279(1):69- Johnstone CN, Mongroo PS, Rich AS, Schupp M, et al. Parvin- 79 beta inhibits breast cancer tumorigenicity and promotes CDK9- mediated peroxisome proliferator-activated receptor gamma 1 Yamaji S, Suzuki A, Sugiyama Y, Koide Y, Yoshida M, phosphorylation. Mol Cell Biol. 2008 Jan;28(2):687-704 Kanamori H, Mohri H, Ohno S, Ishigatsubo Y. A novel integrin- linked kinase-binding protein, affixin, is involved in the early Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, et al. An stage of cell-substrate interaction. J Cell Biol. 2001 Jun integrated genomic analysis of human glioblastoma multiforme. 11;153(6):1251-64 Science. 2008 Sep 26;321(5897):1807-12 Fukuda T, Chen K, Shi X, Wu C. PINCH-1 is an obligate Lange A, Wickström SA, Jakobson M, Zent R, Sainio K, partner of integrin-linked kinase (ILK) functioning in cell shape Fässler R. Integrin-linked kinase is an adaptor with essential modulation, motility, and survival. J Biol Chem. 2003 Dec functions during mouse development. Nature. 2009 Oct 19;278(51):51324-33 15;461(7266):1002-6 Rosenberger G, Jantke I, Gal A, Kutsche K. Interaction of Montanez E, Wickström SA, Altstätter J, Chu H, Fässler R. alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an Alpha-parvin controls vascular mural cell recruitment to vessel

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wall by regulating RhoA/ROCK signalling. EMBO J. 2009 Oct Wickström SA, Lange A, Montanez E, Fässler R. The 21;28(20):3132-44 ILK/PINCH/parvin complex: the kinase is dead, long live the pseudokinase! EMBO J. 2010 Jan 20;29(2):281-91 Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, et al. Systematic sequencing of renal carcinoma reveals inactivation This article should be referenced as such: of histone modifying genes. Nature. 2010 Jan 21;463(7279):360-3 Johnstone CN. PARVB (parvin, beta). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1):34-38. Kimura M, Murakami T, Kizaka-Kondoh S, Itoh M, et al. Functional molecular imaging of ILK-mediated Akt/PKB signaling cascades and the associated role of beta-parvin. J Cell Sci. 2010 Mar 1;123(Pt 5):747-55

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