RhoC (Ras homolog gene family, member C) is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases.[5] It is encoded by the gene RHOC.[6]
Mechanism and function
It is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. It cycles between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades.
Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape and motility. RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskeleton.[7][8][9]
Overexpression of RhoC is associated with cell proliferation and causing tumors to become malignant.[10] It causes degradation and reconstruction of the Extracellular Matrix (ECM) which helps cells escape the tissue they are currently in. It enhances cell motility giving it the ability to become invasive.[11] It has been found to have a direct relationship to advanced tumor stage and metastasis, with increases in stage being related to increases in RhoC expression.[12] RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.[13]
It has also been found to enhance the creation of angiogenic factors such as VEGF, which is necessary for a tumor to become malignant.[12][14]
In a study by Vega,[15] RhoC was knocked out which resulted in cells spreading out wide in all directions. When RhoC was disabled, the cell's abilities to move in a specific direction and migrate was impaired. It also reduced the cell's speed of movement, because it was difficult, and sometimes impossible, to polarize the cell.
Associated Signaling Pathways
RhoC expression has been associated with several signaling pathways and effectors. Here is a list of the ones found so far:
IQGAP1 (IQ-domain GTP-ase Activating Protein): an effector of RhoC to enhance expression of cyclin E and cyclin D1. This resulted in cells being promoted to enter S phase more rapidly [16]
RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers [16][23]
RhoC can be used as a biomarker for judging the metastatic potential of tumors[21][24]
One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC [23]
It has been found that RhoC expression is not important for embryogenesis but it is only important for metastasis, which would make it a good target for treatments.[14]
A RhoC targeted therapy (RV001 by RhoVac) is currently tested in prostate cancer in an ongoing clinical phase 2b program in the US and Europe. Results are expected mid 2022 (Reference: https://clinicaltrials.gov/ct2/show/NCT04114825)
^ abcdefghZhao Y, Zhi-hong Z, Hui-mian X (2010). "RhoC Expression Level Is Correlated with the Clinicopathological Characteristics of Ovarian Cancer and the Expression Levels of ROCK-I, VEGF, and MMP9". Gynecologic Oncology. 116 (3): 563–71. doi:10.1016/j.ygyno.2009.11.015. PMID20022093.
^Genda T, Sakamoto M, Ichida T, Asakura H, Kojiro M, Narumiya S, Hirohashi S (1999). "Cell Motility Mediated by Rho and Rho-Associated Protein Kinase Plays a Critical Role in Intrahepatic Metastasis of Human Hepatocellular Carcinoma". Hepatology. 30 (4): 1027–36. doi:10.1002/hep.510300420. PMID10498656. S2CID35864555.
^ abVan Golen KL, Bao LW, Pan Q, Miller FR, Wu ZF, Merajver SD (2002). "Mitogen Activated Protein Kinase Pathway Is Involved in RhoC GTPase Induced Motility, Invasion and Angiogenesis in Inflammatory Breast Cancer". Clinical & Experimental Metastasis. 19 (4): 301–11. doi:10.1023/A:1015518114931. hdl:2027.42/42584. PMID12090470. S2CID211284.
^ abKleer CG, Griffith KA, Sabel MS, Gallagher G, van Golen KL, Wu ZF, Merajver SD (2005). "RhoC-GTPase Is a Novel Tissue Biomarker Associated with Biologically Aggressive Carcinomas of the Breast". Breast Cancer Research and Treatment. 93 (2): 101–10. doi:10.1007/s10549-005-4170-6. hdl:2027.42/44231. PMID16187229. S2CID9215922.
Maekawa M, Ishizaki T, Boku S, et al. (1999). "Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase". Science. 285 (5429): 895–8. doi:10.1126/science.285.5429.895. PMID10436159.
Shao F, Dixon JE (2004). "YopT is a Cysteine Protease Cleaving Rho Family GTPases". The Genus Yersinia. Advances in Experimental Medicine and Biology. Vol. 529. pp. 79–84. doi:10.1007/0-306-48416-1_14. ISBN0-306-47759-9. PMID12756732.
1cc0: CRYSTAL STRUCTURE OF THE RHOA.GDP-RHOGDI COMPLEX
1cxz: CRYSTAL STRUCTURE OF HUMAN RHOA COMPLEXED WITH THE EFFECTOR DOMAIN OF THE PROTEIN KINASE PKN/PRK1
1dpf: CRYSTAL STRUCTURE OF A MG-FREE FORM OF RHOA COMPLEXED WITH GDP
1ftn: CRYSTAL STRUCTURE OF THE HUMAN RHOA/GDP COMPLEX
1kmq: Crystal Structure of a Constitutively Activated RhoA Mutant (Q63L)
1lb1: Crystal Structure of the Dbl and Pleckstrin homology domains of Dbs in complex with RhoA
1ow3: Crystal Structure of RhoA.GDP.MgF3-in Complex with RhoGAP
1s1c: Crystal structure of the complex between the human RhoA and Rho-binding domain of human ROCKI
1tx4: RHO/RHOGAP/GDP(DOT)ALF4 COMPLEX
1x86: Crystal Structure of the DH/PH domains of Leukemia-associated RhoGEF in complex with RhoA
1xcg: Crystal Structure of Human RhoA in complex with DH/PH fragment of PDZRHOGEF
1z2c: Crystal structure of mDIA1 GBD-FH3 in complex with RhoC-GMPPNP
2gcn: Crystal structure of the human RhoC-GDP complex
2gco: Crystal structure of the human RhoC-GppNHp complex
2gcp: Crystal structure of the human RhoC-GSP complex
External links
Laudanna C (2008). "RhoC". AfCS-Nature Molecule Pages. doi:10.1038/mp.a002065.01 (inactive 1 November 2024).{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
