RhoC

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.{{cite journal |vauthors=Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R | title = Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC | journal = Oncogene | volume = 29 | issue = 16 | pages = 2441–8 |date=April 2010 | pmid = 20101212 | doi = 10.1038/onc.2009.515 | s2cid = 25556221 | doi-access = }}{{cite journal | vauthors = Jaffe AB, Hall A | year = 2005 | title = Rho GTPases: Biochemistry and Biology | journal = Annual Review of Cell and Developmental Biology | volume = 21 | pages = 247–69 | doi = 10.1146/annurev.cellbio.21.020604.150721 | pmid = 16212495 }}{{cite journal | vauthors = Vega FM, Ridley AJ | year = 2008| title = Rho GTPases in Cancer Cell Biology | journal = FEBS Letters | volume = 582 | issue = 14| pages = 2093–2101 | doi = 10.1016/j.febslet.2008.04.039 | pmid = 18460342| doi-access = free | bibcode = 2008FEBSL.582.2093V}}

Overexpression of RhoC is associated with cell proliferation and causing tumors to become malignant.{{cite journal|vauthors=Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I|title=Up-Regulation of Small GTPases, RhoA and RhoC, Is Associated with Tumor Progression in Ovarian Carcinoma|journal=Laboratory Investigation|volume=83|issue=6|date=June 2003|pages=861–870|doi=10.1097/01.LAB.0000073128.16098.31|pmid=12808121|s2cid=22119772|doi-access=free}} 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.{{cite journal|vauthors=Ikoma T, Takahashi T, Nagano S, Li YM, Ohno Y, Ando K, Fujiwara T, Fujiwara H, Kosai K|title=A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice|journal=Clinical Cancer Research|volume=10|issue=3|date=February 2004|pages=1192–1200|doi=10.1158/1078-0432.ccr-03-0275 |pmid=14871999|doi-access=free}} 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.{{cite journal | vauthors = Zhao Y, Zhi-hong Z, Hui-mian X | year = 2010| title = RhoC Expression Level Is Correlated with the Clinicopathological Characteristics of Ovarian Cancer and the Expression Levels of ROCK-I, VEGF, and MMP9 | journal = Gynecologic Oncology | volume = 116 | issue = 3| pages = 563–71 | doi = 10.1016/j.ygyno.2009.11.015 | pmid = 20022093}} RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.{{cite journal |vauthors=Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW | title = RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis | journal = Genes Dev. | volume = 19 | issue = 17 | pages = 1974–9 |date=September 2005 | pmid = 16107613 | pmc = 1199568 | doi = 10.1101/gad.1310805 }}

It has also been found to enhance the creation of angiogenic factors such as VEGF, which is necessary for a tumor to become malignant.{{cite journal | vauthors = Srivastava S, Ramdass B, Nagarajan S, Rehman M, Mukherjee G, Krishna S | year = 2010| title = Notch1 Regulates the Functional Contribution of RhoC to Cervical Carcinoma Progression | journal = British Journal of Cancer | volume = 102 | issue = 1| pages = 196–205 | doi = 10.1038/sj.bjc.6605451 | pmid = 19953094| pmc = 2813755| doi-access = free }}

In a study by Vega,{{cite journal | vauthors = Vega FM, Fruhwirth G, Ng T, Ridley AJ | year = 2011| title = RhoA and RhoC Have Distinct Roles in Migration and Invasion by Acting through Different Targets | journal = The Journal of Cell Biology | volume = 193 | issue = 4| pages = 655–65 | doi = 10.1083/jcb.201011038 | pmid = 21576392| pmc = 3166870| doi-access = free }} 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.

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 {{cite journal | vauthors = Wu Y, Tao Y, Chen Y, Xu W | title = RhoC Regulates the Proliferation of Gastric Cancer Cells through Interaction with IQGAP1 | journal = PLOS ONE | year = 2012 | volume = 7 | issue = 11| page = e48917 | doi = 10.1371/journal.pone.0048917 | pmid = 23145020 | pmc = 3492142 | bibcode = 2012PLoSO...748917W | doi-access = free }}
• ROCK-1 {{cite journal | vauthors = Genda T, Sakamoto M, Ichida T, Asakura H, Kojiro M, Narumiya S, Hirohashi S | year = 1999| title = Cell Motility Mediated by Rho and Rho-Associated Protein Kinase Plays a Critical Role in Intrahepatic Metastasis of Human Hepatocellular Carcinoma | journal = Hepatology | volume = 30 | issue = 4| pages = 1027–36 | doi = 10.1002/hep.510300420 | pmid = 10498656| s2cid = 35864555| doi-access = }}
• MMP9: necessary for ECM regulation
• FMNL3: a Formin downstream target, which is used to regulate where Rac1 is active
• MAPK pathway: upregulating VEGF, Basic fibroblastic growth factors, and interleukins 6 and 8 expression {{cite journal | vauthors = Van Golen KL, Bao LW, Pan Q, Miller FR, Wu ZF, Merajver SD | year = 2002 | title = Mitogen Activated Protein Kinase Pathway Is Involved in RhoC GTPase Induced Motility, Invasion and Angiogenesis in Inflammatory Breast Cancer | journal = Clinical & Experimental Metastasis | volume = 19 | issue = 4| pages = 301–11 |pmid= 12090470 |doi= 10.1023/A:1015518114931| hdl = 2027.42/42584 | s2cid = 211284 | hdl-access = free }}
• Notch1
• PI3K/AKt pathway: Proliferation and invasiveness {{cite journal | vauthors = Sun HW, Tong SL, He J, Wang Q, Zou L, Ma SJ, Tan HY, Luo JF, Wu HX | year = 2007| title = RhoA and RhoC -siRNA Inhibit the Proliferation and Invasiveness Activity of Human Gastric Carcinoma by Rho/PI3K/Akt Pathway | journal = World Journal of Gastroenterology | volume = 13 | issue = 25| pages = 3517–22 | doi = 10.3748/wjg.v13.i25.3517 | doi-broken-date = 3 December 2024| pmid = 17659701| pmc = 4146790 | doi-access = free}}
• Pyk2: metastasis {{cite journal | vauthors = Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, Tsukada T | display-authors = etal | year = 2008| title = RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer | journal = Cancer Research | volume = 68 | issue = 18| pages = 7613–20 | doi = 10.1158/0008-5472.CAN-07-6700 | pmid = 18794150 | pmc = 2741300 | doi-access = free }}

RhoC has been found to be overexpressed in:

• Lung Cancer
• Gastric Cancer
• Ovarian cancer
• Breast Cancer {{cite journal | vauthors = Kleer CG, Griffith KA, Sabel MS, Gallagher G, van Golen KL, Wu ZF, Merajver SD | year = 2005| title = RhoC-GTPase Is a Novel Tissue Biomarker Associated with Biologically Aggressive Carcinomas of the Breast | journal = Breast Cancer Research and Treatment | volume = 93 | issue = 2| pages = 101–10 | doi = 10.1007/s10549-005-4170-6 | pmid = 16187229| hdl = 2027.42/44231 | s2cid = 9215922| hdl-access = free }}
• Hepatocellular Cancer {{cite journal | vauthors = Wang W, Wu F, Fang F, Tao Y, Yang L | year = 2008| title = RhoC Is Essential for Angiogenesis Induced by Hepatocellular Carcinoma Cells via Regulation of Endothelial Cell Organization | journal = Cancer Science | volume = 99 | issue = 10| pages = 2012–18 | doi = 10.1111/j.1349-7006.2008.00902.x | pmid = 19016761| s2cid = 23715139| doi-access = | pmc = 11160101 }}
• Pancreatic Cancer
• Colorectal Cancer {{cite journal | vauthors = Wang H, Zhao G, Liu X, Sui A, Yang K, Yao R, Wang Z, Shi Q | year = 2010 | title = Silencing of RhoA and RhoC Expression by RNA Interference Suppresses Human Colorectal Carcinoma Growth in Vivo | journal = Journal of Experimental & Clinical Cancer Research | volume = 29 | issue = 1 | page = 123 | doi = 10.1186/1756-9966-29-123 | pmid = 20828398 | pmc = 2945978 | doi-access = free }}
• Cancer of the Urogenital System
• Melanoma
• Prostate Cancer
• Cervical Carcinoma

RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers

RhoC can be used as a biomarker for judging the metastatic potential of tumors{{cite journal | vauthors = Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, Leung S | display-authors = etal | title = Ovarian Carcinoma Subtypes Are Different Diseases: Implications for Biomarker Studies | journal = PLOS Medicine | year = 2008 | volume = 5 | issue = 12| page = e232 | doi = 10.1371/journal.pmed.0050232 | pmid = 19053170 | pmc = 2592352 | doi-access = free }}

One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC

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.

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)

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{{refbegin|40em}}

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• {{cite journal|vauthors=Arthur WT, Ellerbroek SM, Der CJ, etal |title=XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. |journal=J. Biol. Chem. |volume=277 |issue= 45 |pages= 42964–72 |year= 2003 |pmid= 12221096 |doi= 10.1074/jbc.M207401200 |doi-access= free}}
• {{cite journal|vauthors=Chardin P, Madaule P, Tavitian A |title=Coding sequence of human rho cDNAs clone 6 and clone 9. |journal=Nucleic Acids Res. |volume=16 |issue= 6 |pages= 2717 |year= 1988 |pmid= 3283705 |doi=10.1093/nar/16.6.2717 | pmc=336400}}
• {{cite journal|vauthors=Clark EA, Golub TR, Lander ES, Hynes RO |title=Genomic analysis of metastasis reveals an essential role for RhoC. |journal=Nature |volume=406 |issue= 6795 |pages= 532–5 |year= 2000 |pmid= 10952316 |doi= 10.1038/35020106|s2cid=4301092 }}
• {{cite journal|vauthors=Diviani D, Soderling J, Scott JD |title=AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation. |journal=J. Biol. Chem. |volume=276 |issue= 47 |pages= 44247–57 |year= 2001 |pmid= 11546812 |doi= 10.1074/jbc.M106629200 |doi-access= free}}
• {{cite journal|vauthors=Kleer CG, van Golen KL, Zhang Y, etal |title=Characterization of RhoC expression in benign and malignant breast disease: a potential new marker for small breast carcinomas with metastatic ability. |journal=Am. J. Pathol. |volume=160 |issue= 2 |pages= 579–84 |year= 2002 |pmid= 11839578 |doi= 10.1016/S0002-9440(10)64877-8| pmc=1850656}}
• {{cite journal|vauthors=Madaule P, Axel R |title=A novel ras-related gene family. |journal=Cell |volume=41 |issue= 1 |pages= 31–40 |year= 1985 |pmid= 3888408 |doi=10.1016/0092-8674(85)90058-3|s2cid=32708060 }}
• {{cite journal|vauthors=Maekawa M, Ishizaki T, Boku S, etal |title=Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. |journal=Science |volume=285 |issue= 5429 |pages= 895–8 |year= 1999 |pmid= 10436159 |doi=10.1126/science.285.5429.895}}
• {{cite journal|vauthors=Reid T, Furuyashiki T, Ishizaki T, etal |title=Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain. |journal=J. Biol. Chem. |volume=271 |issue= 23 |pages= 13556–60 |year= 1996 |pmid= 8662891 |doi=10.1074/jbc.271.23.13556 |doi-access=free}}
• {{cite book|vauthors=Shao F, Dixon JE |title=The Genus Yersinia |chapter=YopT is a Cysteine Protease Cleaving Rho Family GTPases |series=Advances in Experimental Medicine and Biology |date=2004 |volume=529 |pages= 79–84 |pmid= 12756732 |doi=10.1007/0-306-48416-1_14|isbn=0-306-47759-9 }}
• {{cite journal|vauthors=van Golen KL, Bao LW, Pan Q, etal |title=Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer. |journal=Clin. Exp. Metastasis |volume=19 |issue= 4 |pages= 301–11 |year= 2002 |pmid= 12090470 |doi=10.1023/A:1015518114931 |hdl=2027.42/42584 |s2cid=211284 |url=https://deepblue.lib.umich.edu/bitstream/2027.42/42584/1/10585_2004_Article_397672.pdf|hdl-access=free }}
• {{cite journal|vauthors=Wheeler AP, Ridley AJ |title=Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. |journal=Exp. Cell Res. |volume=301 |issue= 1 |pages= 43–9 |year= 2004 |pmid= 15501444 |doi= 10.1016/j.yexcr.2004.08.012}}

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{{PDB Gallery|geneid=389}}

• {{cite journal | doi = 10.1038/mp.a002065.01 | title=RhoC | year=2008 | journal=AfCS-Nature Molecule Pages | vauthors=Laudanna C| doi-broken-date=1 November 2024 }}
• {{cite web |url=http://www.signaling-gateway.org/molecule/query?afcsid=A002065 |title=RhoC : Abstract : UCSD-Nature Molecule Pages |access-date=2009-06-16 |archive-date=2021-12-04 |archive-url=https://web.archive.org/web/20211204141528/http://www.signaling-gateway.org/molecule/query?afcsid=A002065 |url-status=dead }}

{{Rho family of GTPases}}