Alternative titles; symbols
HGNC Approved Gene Symbol: PSMD10
Cytogenetic location: Xq22.3 Genomic coordinates (GRCh38): X:108,084,207-108,091,542 (from NCBI)
Ubiquitinated proteins are degraded by a 26S ATP-dependent protease. The protease is composed of a 20S catalytic proteasome and PA700, a 700-kD regulatory complex (see PSMC1, 602706) that includes PSMD10 (Hori et al., 1998).
Hori et al. (1998) determined the partial protein sequences of bovine p28 and p40.5 (PSMD13; 603481), 2 components of PA700. By searching a sequence database, they identified cDNAs encoding the human p28 and p40.5 homologs, and they cloned the cDNAs from a U937 monocyte cDNA library. The predicted 226-amino acid human p28 protein contains 5 ankyrin repeats, which are thought to function in protein-protein interactions. Using computerized homology searches, Hori et al. (1998) identified Nas6, an S. cerevisiae gene encoding a protein with 38% identity to p28. Northern blot analysis revealed that p28 was expressed as a 1.3-kb mRNA in all human tissues tested.
Hori et al. (1998) found that disruption of yeast Nas6 had no effect on cell viability.
Man et al. (2010) found that expression of constitutively active mutant RAS (HRAS; 190020) increased gankyrin mRNA and protein expression and induced a tumorigenic phenotype in transfected NIH3T3 mouse fibroblasts. Knockdown of gankyrin reversed RAS-induced transformation and tumorigenesis. Gankyrin was highly expressed in human lung cancers expressing RAS with oncogenic mutations, and gankyrin expression was higher in adenocarcinomas than in squamous carcinomas. Knockdown and molecular studies performed predominantly with mouse cells revealed that gankyrin increased interaction between Rhoa (165390) and its inhibitor Rhogdi (ARHGDIA; 601925), resulting in elevated Akt (see 164730) activation via the Rhoa-Rock (see 601702)-Pten (601728) pathway. Knockdown of Rock or deletion of Pten reversed gankyrin-mediated Akt activation.
Dong et al. (2011) stated that p28(GANK) is highly expressed in human hepatocellular carcinoma (HCC) cells. Using a reporter gene assay with HepG2 and HEK293 cells, they found that the growth factors EGF (131530) and HGF (142409), in addition to RAS, elevated p28(GANK) mRNA and protein expression in a dose-dependent manner. Molecular and inhibitor studies revealed that this activation of p28(GANK) occurred through the PI3 kinase (see 601232)-AKT signaling pathway. In 40 primary HCC samples, p28(GANK) protein levels correlated with AKT activation. Beta-catenin (see 116806) and MYC (190080) also activated p28(GANK) expression, and p28(GANK) increased beta-catenin signaling in a positive-feedback loop. p28(GNAK) appeared to increase beta-catenin signaling by releasing it from cytoskeletal sequestration in complex with E-cadherin (CDH1; 192090).
Zhen et al. (2013) found that gankyrin was highly overexpressed in human breast cancers and that gankyrin expression correlated strongly with lymph node metastasis. In cultured human breast cancer cells, knockdown of gankyrin reduced cell migration and increased cell adhesion, with formation of large focal adhesions. Expression of constitutively active RAC1 (602048) reversed the effects of gankyrin knockdown. Overexpression of gankyrin accelerated focal adhesion turnover and increased cell migration.
Hartz (2012) mapped the PSMD10 gene to chromosome Xq22.32 based on an alignment of the PSMD10 sequence (GenBank AB009619) with the genomic sequence (GRCh37).
Dong, L., Yang, G., Pan, Y., Chen, Y., Tan, Y., Dai, R., Ren, Y., Fu, J., Wang, H. The oncoprotein p28(GANK) establishes a positive feedback loop in beta-catenin signaling. Cell Res. 21: 1248-1261, 2011. [PubMed: 21691299] [Full Text: https://doi.org/10.1038/cr.2011.103]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/26/2012.
Hori, T., Kato, S., Saeki, M., DeMartino, G. N., Slaughter, C. A., Takeuchi, J., Toh-e, A., Tanaka, K. cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome. Gene 216: 113-122, 1998. [PubMed: 9714768] [Full Text: https://doi.org/10.1016/s0378-1119(98)00309-6]
Man, J.-H., Liang, B., Gu, Y.-X., Zhou, T., Li, A.-L., Li, T., Jin, B.-F., Bai, B., Zhang, H.-Y., Zhang, W.-N., Li, W.-H., Gong, W.-L., Li, H.-Y., Zhang, X.-M. Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells. J. Clin. Invest. 120: 2829-2841, 2010. [PubMed: 20628200] [Full Text: https://doi.org/10.1172/JCI42542]
Zhen, C., Chen, L., Zhao, Q., Liang, B., Gu, Y.-X., Bai, Z., Wang, K., Xu, X., Han, Q., Fang, D., Wang, S., Zhou, T., Xia, Q., Gong, W.-I., Wang, N., Li, H.-Y., Jin, B.-F., Man, J. Gankyrin promotes breast cancer cell metastasis by regulating Rac1 activity. Oncogene 32: 3452-3460, 2013. [PubMed: 22890318] [Full Text: https://doi.org/10.1038/onc.2012.356]