Alternative titles; symbols
HGNC Approved Gene Symbol: RHOC
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:112,701,131-112,707,408 (from NCBI)
The Ras superfamily of small GTP-binding proteins comprises a large group of proteins involved in signal transduction, proliferation, vesicle trafficking, and regulation of the actin cytoskeleton. Madaule and Axel (1985) identified a new family of Ras genes, the Rho genes, related to a gene originally identified in Aplysia. Human cDNAs encoding 3 Rho, or ARH (Aplysia Ras-related homolog), proteins were isolated and designated H6 (RHOB; 165370), H9, and H12 (RHOA; 165390). Chardin et al. (1988) reported the complete H9 coding sequence and renamed the gene RhoC. The predicted protein is 193 amino acids long. The 3 human Rho proteins display approximately 30% sequence identity with Ras proteins. Most of the homology is found within 4 regions corresponding to the GTP-binding site. Fagan et al. (1994) recovered a RhoC cDNA from an adult retina library.
The small guanosine triphosphatase Rho regulates remodeling of the actin cytoskeleton during cell morphogenesis and motility. In their Figure 3C, Maekawa et al. (1999) diagrammed proposed signaling pathways for Rho-induced remodeling of the actin cytoskeleton. They demonstrated that active Rho signals to its downstream effector ROCK (601702), which phosphorylates and activates LIM kinase (see 601329). LIM kinase, in turn, phosphorylates cofilin (601442), inhibiting its actin-depolymerizing activity.
Clark et al. (2000) used an in vivo selection scheme to select highly metastatic melanoma cells. By analyzing these cells on DNA arrays, they defined a pattern of gene expression that correlates with progression to a metastatic phenotype. In particular, Clark et al. (2000) showed enhanced expression of several genes involved in extracellular matrix assembly and of a second set of genes that regulate, either directly or indirectly, the actin-based cytoskeleton. Clark et al. (2000) found that RhoC enhances metastasis when overexpressed, whereas a dominant-negative Rho inhibits metastasis. Analysis of the phenotype of cells expressing dominant-negative Rho or RhoC indicates that RhoC is important in tumor cell invasion. The genomic approach allowed Clark et al. (2000) to identify families of genes involved in a process, not just single genes, and could indicate which molecular and cellular events might be important in complex biologic processes such as metastasis.
Crystal Structure
Rose et al. (2005) presented the crystal structure of RhoC in complex with the regulatory N terminus of mouse diaphanous-1 (DIAPH1; 602121) containing the GBD/FH3 region, an all-helical structure with armadillo repeats. Rho uses its 'switch' regions for interacting with 2 subdomains of GBD/FH3. Rose et al. (2005) showed that the FH3 domain of Diaph1 forms a stable dimer and identified the diaphanous autoregulatory domain (DAD)-binding site. Although binding of Rho and DAD on the N-terminal fragment of Diaph1 are mutually exclusive, their binding sites are only partially overlapping.
Cannizzaro et al. (1990) mapped the H9 member of the ARH family (RHOC) to 5q33-qter by study of rodent-human hybrids and in situ hybridization. The latter technique showed a clustering of grains in 5q31-qter. The gene was noted to cosegregate with the CFS1 gene (120420) in human/rodent somatic cell hybrids carrying partial chromosomes 5, together with other human chromosomes. After the CSF1 locus was reassigned to 1p21-p13, Morris et al. (1993) reexamined the assignment of RHOC and showed that it also was present in hybrids retaining chromosome 1. With hybrids carrying partial 1p, they mapped the gene to 1p31-p13. Fluorescence in situ hybridization regionalized the gene to 1p21-p13.
Cannizzaro, L. A., Madaule, P., Hecht, F., Axel, R., Croce, C. M., Huebner, K. Chromosome localization of human ARH genes, a ras-related gene family. Genomics 6: 197-203, 1990. [PubMed: 2407642] [Full Text: https://doi.org/10.1016/0888-7543(90)90557-b]
Chardin, P., Madaule, P., Tavitian, A. Coding sequence of human rho cDNAs clone 6 and clone 9. Nucleic Acids Res. 16: 2717 only, 1988. [PubMed: 3283705] [Full Text: https://doi.org/10.1093/nar/16.6.2717]
Clark, E. A., Golub, T. R., Lander, E. S., Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406: 532-535, 2000. Note: Erratum: Nature 411: 974 only, 2001. [PubMed: 10952316] [Full Text: https://doi.org/10.1038/35020106]
Fagan, K. P., Oliveira, L., Pittler, S. J. Sequence of rho small GTP-binding protein cDNAs from human retina and identification of novel 5-prime end cloning artifacts. Exp. Eye Res. 59: 235-237, 1994. [PubMed: 7835413] [Full Text: https://doi.org/10.1006/exer.1994.1102]
Madaule, P., Axel, R. A novel ras-related gene family. Cell 41: 31-40, 1985. [PubMed: 3888408] [Full Text: https://doi.org/10.1016/0092-8674(85)90058-3]
Maekawa, M., Ishizaki, T., Boku, S., Watanabe, N., Fujita, A., Iwamatsu, A., Obinata, T., Ohashi, K., Mizuno, K., Narumiya, S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285: 895-898, 1999. [PubMed: 10436159] [Full Text: https://doi.org/10.1126/science.285.5429.895]
Morris, S. W., Valentine, M. B., Kirstein, M. N., Huebner, K. Reassignment of the human ARH9 RAS-related gene to chromosome 1p13-p21. Genomics 15: 677-679, 1993. [PubMed: 8468062] [Full Text: https://doi.org/10.1006/geno.1993.1124]
Rose, R., Weyand, M., Lammers, M., Ishizaki, T., Ahmadian, M. R., Wittinghofer, A. Structural and mechanistic insights into the interaction between Rho and mammalian Dia. (Letter) Nature 435: 513-518, 2005. [PubMed: 15864301] [Full Text: https://doi.org/10.1038/nature03604]