Brick1 Is an Essential Regulator of Actin Cytoskeleton Required for Embryonic Development and Cell Transformation

Abstract

Brick1 (Brk1) is the less-studied component of the Wave/Scar pathway involved in the branched nucleation of actin fibers. The clinical relevance of Brk1 is emphasized by correlative data showing that Von Hippel-Lindau (VHL) patients that also lose the BRK1 gene are protected against the development of tumors. This contrasts with recent evidence suggesting that the Wave complex may function as an invasion suppressor in epithelial cancers. Here, we show that the downregulation of Brk1 results in abnormal actin stress fiber formation and vinculin distribution and loss of Arp2/3 and Wave proteins at the cellular protrusions. Brk1 is required for cell proliferation and cell transformation by oncogenes. In addition, Brk1 downregulation results in defective directional migration and invasive growth in renal cell carcinoma cells as well as in other tumor cell types. Finally, genetic ablation of Brk1 results in dramatic defects in embryo compaction and development, suggesting an essential role for this protein in actin dynamics. Thus, genetic loss or inhibition of BRK1 is likely to be protective against tumor development due to proliferation and motility defects in affected cells. Cancer Res; 70(22); 9349-59.

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

“…APELA annotation has now changed from lncRNA (GRCh37) to mRNA (GRCh38), highlighting the dynamic nature of genome annotations . Other biological roles attributed to smORFs include sarcoendoplasmic reticulum calcium transport ATPase (SERCA) machinery regulation, regulation of ribosome-protein complexes, prevention of cell death, and regulation of transcription (Hashimoto et al 2001;Galindo et al 2007;Kondo et al 2007;Hanyu-Nakamura et al 2008;Escobar et al 2010;Magny et al 2013;Anderson et al 2015;Pueyo et al 2016b;D'Lima et al 2017;Matsumoto et al 2017a, b). Moreover, smORFs have been detected within the mitochondrial genome, encoding short circulating peptides acting in a hormone-like manner (Yen et al 2013;Lee et al 2016;Kim et al 2017;Okada et al 2017).…”

Von Hippel-Lindau Disease: A Genetic and Clinical Review

“…Loss of this gene is protective against tumors by inducing defects in cell migration in RCC and other tumors. 36 This mapping might also explain the genotype-phenotype correlation in VHL patients with retinal hemangioblastomas.…”

“…Large deletion of these genes may be protective from tumor formation while point mutations would not affect these genes. 36 For example, Brk1 maps near Von Hippel-Lindau Disease 379 the VHL gene and acts as a regulator of the actin cytoskeleton. Loss of this gene is protective against tumors by inducing defects in cell migration in RCC and other tumors.…”

FusionFinder: A Software Tool to Identify Expressed Gene Fusion Candidates from RNA-Seq Data

“…The BRK1 gene ( BRICK1 , C3orf10 or HSPC300 ) lies upstream of VHL on chromsome 17 and is involved in the branched nucleation of actin fibres. Although no fusions of the two genes have to date been reported, co-deletion of BRK1 has been shown to alter the prevalence and severity of renal-cell carcinoma in patients with VHL deletion [30], [31]. Such co-deletion has been attributed to Alu -mediated recombination since the genes lie in a region of high Alu density [30] and it is likely that gene fusion could occur by a similar mechanism with deletion of the intergenic region.…”

“…Although no fusions of the two genes have to date been reported, co-deletion of BRK1 has been shown to alter the prevalence and severity of renal-cell carcinoma in patients with VHL deletion [30], [31]. Such co-deletion has been attributed to Alu -mediated recombination since the genes lie in a region of high Alu density [30] and it is likely that gene fusion could occur by a similar mechanism with deletion of the intergenic region. This is consistent with the transcript breakpoint in isoform 2, which appears to involve an intra-exonic break in the C3orf10 gene (sequences available in File S1), arguing against an RNA-splicing mechanism.…”