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RHO GTPase-ACTIVATING PROTEIN 8; ARHGAP8

RHO GTPase-ACTIVATING PROTEIN 8; ARHGAP8

Alternative titles; symbolsGTPase-ACTIVATING PROTEIN, RHO, 8BCH DOMAIN-CONTAINING, PROLINE-RICH, AND CDC42GAP-LIKE PROTEIN 1; BPGAP1HGNC Approved Gene Symbol: AR...

Alternative titles; symbols

  • GTPase-ACTIVATING PROTEIN, RHO, 8
  • BCH DOMAIN-CONTAINING, PROLINE-RICH, AND CDC42GAP-LIKE PROTEIN 1; BPGAP1

HGNC Approved Gene Symbol: ARHGAP8

Cytogenetic location: 22q13.31 Genomic coordinates (GRCh38): 22:44,752,574-44,862,783 (from NCBI)

▼ Description
Small GTPases control cell dynamics during growth and development. Proteins with a GTPase-activating domain (GAP) domain, such as ARHGAP8, catalyze the conversion of small GTPases from their active, GTP-bound form to their inactive, GDP-bound form (Lua and Low, 2004).

▼ Cloning and Expression
By searching databases for sequences similar to CDC42GAP (ARHGAP1; 602732), followed by PCR of a mammary carcinoma cell line, Shang et al. (2003) cloned a splice variant of ARHGAP8, which they designated BPGAP1. The deduced 433-amino acid protein contains a BNIP2 (603292) and CDC42GAP homology (BCH) domain, followed by a proline-rich region and a C-terminal GAP domain with a conserved arginine necessary for catalytic activity. Database analysis identified 3 possible splice variants encoding BPGAP1-like proteins that differ in their N-terminal halves. RT-PCR detected expression of BPGAP1 in all human cell lines and mouse tissues tested.

Using a candidate gene approach to identify putative tumor suppressors in a region of chromosome 22 involved in loss of heterozygosity, Johnstone et al. (2004) identified the ARHGAP8 gene. They characterized 3 different ARHGAP8 transcripts resulting from alternative splicing of exon 5. The variant containing exon 5 encodes a deduced 464-amino acid protein with a calculated molecular mass of 53.5 kD. This isoform contains a putative N-terminal BCH lipid-binding domain, a central proline-rich SH3 domain-binding motif, and a C-terminal RhoGAP domain with a conserved catalytic arginine. The variant lacking exon 5 encodes a protein with a 31-amino acids deletion in the BCH domain, and the variant with a truncation of exon 5 encodes a protein with a 5-amino acid deletion in the BCH domain. Northern blot analysis detected ARHGAP8 expression in colon, skeletal muscle, small intestine, stomach, and testis, with highest expression in kidney and placenta. Johnstone et al. (2004) also identified mouse Arhgap8. The mouse gene lacks an exon equivalent to human exon 5 and encodes a 325-amino acid protein that shares 80% identity with human ARHGAP8. Johnstone et al. (2004) noted that a mouse gene reported as Arhgap8 by Shan et al. (2003) actually represents a distinct gene, Prr5 (609406), located immediately centromeric to Arhgap8.

▼ Gene Function
Shang et al. (2003) found that BPGAP1 selectively enhanced RhoA (ARHA; 165390) GTPase activity in vitro, although it also interacted strongly with CDC42 (116952) and RAC1 (602048). Pull-down and coimmunoprecipitation studies showed that BPGAP1 formed homophilic and heterophilic complexes with other BCH domain-containing proteins. Epitope-tagged BPGAP1 induced pseudopodia and increased cell mobility in a transfected breast cancer cell line. Formation of pseudopodia required the BCH and GAP domains of BPGAP1, but not the proline-rich region. BPGAP1-induced pseudopodia formation was differentially inhibited by coexpression of a constitutively active RhoA mutant or by dominant-negative mutants of CDC42 and RAC1. A BPGAP1 mutant without the proline-rich region failed to increase cell migration despite the induction of pseudopodia.

By protein precipitations and matrix-assisted laser desorption/ionization mass spectrometry, Lua and Low (2004) found that BPGAP1 interacted directly with cortactin (EMS1; 164765) in several human cell lines. Progressive deletion studies indicated that the SH3 domain of cortactin interacted directly with the proline-rich motif at amino acids 182 to 189 of BPGAP1. Cotransfection of human embryonic 293T cells with cortactin and BPGAP1 resulted in colocalization of the 2 proteins at the cell periphery and enhanced cell migration. Substitution of pro184 and pro186 in BPGAP1 with alanines abolished the interaction, and mutant BPGAP1 failed to facilitate translocation of cortactin to the periphery or enhance cell migration.

▼ Gene Structure
Johnstone et al. (2004) determined that the ARHGAP8 gene contains 13 exons and spans 110 kb. Exon 1 is embedded in a CpG island.

▼ Mapping
By genomic sequence analysis, Johnstone et al. (2004) mapped the ARHGAP8 gene to chromosome 22q13.31, immediately centromeric to the PRR5 gene. They mapped the mouse Arhgap8 gene to chromosome 15E2, a region that shows homology of synteny to human chromosome 22q13.

Tags: 22q13.31