PARVB (parvin, beta)

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 5 x 108 cpm / mg (Johnstone C.N., unpublished).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

	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)].

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