RHOC

RHOC
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1Z2C, 2GCN, 2GCO, 2GCP
Identifikatori
Aliasi	RHOC
Vanjski ID-jevi	OMIM: 165380 MGI: 106028 HomoloGene: 90945 GeneCards: RHOC
Lokacija gena (čovjek) Hrom. Hromosom 1 (čovjek)[1] Bend 1p13.2 Početak 112,701,127 bp[1] Kraj 112,707,434 bp[1]
Lokacija gena (miš) Hrom. Hromosom 3 (miš)[2] Bend 3|3 F2.2 Početak 104,695,691 bp[2] Kraj 104,701,775 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • nucleotide binding • GTP binding • GO:0001948, GO:0016582 vezivanje za proteine • signal transducer activity • GO:0006184 GTPase activity Ćelijska komponenta • citosol • ćelijska membrana • cleavage furrow • Egzosom • membrana • jedro • intracellular anatomical structure • stereocilium Biološki proces • positive regulation of I-kappaB kinase/NF-kappaB signaling • skeletal muscle satellite cell migration • regulation of small GTPase mediated signal transduction • apical junction assembly • wound healing, spreading of cells • positive regulation of lipase activity • small GTPase mediated signal transduction • positive regulation of protein homooligomerization • mitotic cytokinesis • G protein-coupled receptor signaling pathway Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	389	11853
Ensembl	ENSG00000155366	ENSMUSG00000002233
UniProt	P08134 Q5JR06	Q62159
RefSeq (mRNK)	NM_175744 NM_001042678 NM_001042679	NM_001291859 NM_007484
RefSeq (bjelančevina)	NP_001036143 NP_001036144 NP_786886	NP_001278788 NP_031510
Lokacija (UCSC)	Chr 1: 112.7 – 112.71 Mb	Chr 3: 104.7 – 104.7 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

RhoC (član C Ras porodice genskih homologa) jest mali (~21 kDa) signalni G-protein (GTPaza), koji je kod ljudi kodiran genom RHOCsa hromosoma 1. Član je proteinske porodice Rac, potporodice u porodici Rho porodica GTPaza.^[5][6]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 193 aminokiseline, a molekulska težina 22.006 Da.^[7]

• C: Cistein
• D: Asparaginska kiselina
• E: Glutaminska kiselina
• F: Fenilalanin
• G: Glicin
• H: Histidin
• I: Izoleucin
• K: Lizin
• L: Leucin
• M: Metionin
• N: Asparagin
• P: Prolin
• Q: Glutamin
• R: Arginin
• S: Serin
• T: Treonin
• V: Valin
• W: Triptofan
• Y: Tirozin

10		20		30		40		50
MAAIRKKLVI		VGDGACGKTC		LLIVFSKDQF		PEVYVPTVFE		NYIADIEVDG
KQVELALWDT		AGQEDYDRLR		PLSYPDTDVI		LMCFSIDSPD		SLENIPEKWT
PEVKHFCPNV		PIILVGNKKD		LRQDEHTRRE		LAKMKQEPVR		SEEGRDMANR
ISAFGYLECS		AKTKEGVREV		FEMATRAGLQ		VRKNKRRRGC		PIL

Mehanizam i funkcija

RhoC je preniliran na svom C-terminalu, i lokalizira se u citoplazmi i plazmamembrani. Smatra se da je važan u pokretljivosti ćelija. Kruži između neaktivnog GDP-vezanog i aktivnog GTP-vezanog stanja i funkcionira kao molekulski prekidač u kaskadama transdukcija signala.

Rho proteini podstiču reorganizaciju aktinskog citoskeleta i regulišu oblik i pokretljivost ćelija. RhoC može aktivirati formine kao što su mDia1 i FMNL2 za remodeliranje citoskeleta.^[8][9][10]

Prekomjerna ekspresija RhoC povezana je s proliferacijom ćelija i izazivanjem malignosti tumora.^[11] Prouzrokuje degradaciju i rekonstrukciju vanćelijskog matriksa (ECM) koji pomaže ćelijama da migriraju iz tkiva u kojem se trenutno nalaze. Pospješuje pokretljivost ćelija dajući im mogućnost da postanu invazivne.^[12] Utvrđeno je da ima direktnu vezu sa uznapredovalim stadijem tumora i metastazama, pri čemu je povećanje stadija povezano sa povećanjem ekspresije RhoC.^[13] Miševi s nedostatkom RhoC i dalje mogu razviti tumore, ali oni ne uspijevaju metastazirati, a tvrdu+i se da je RhoC neophodan za metastaze.^[14] Također je utvrđeno da pojačava stvaranje angiogenih faktora kao što je VEGF, koji je neophodan da tumor postane maligni.^[13][15] In a study by Vega,^[16] RhoC was knocked out which resulted in cells spreading out wide in all directions. When RhoC je bio onemogućen, sposobnost ćelije da se kreće u određenom smjeru i migrira bila je narušena. Također je smanjio brzinu kretanja ćelije, jer je bilo teško, a ponekad i nemoguće, polarizirati ćeliju.

Povezani signalni putevi

Ekspresija RhoC-a povezana je sa nekoliko signalnih puteva i efektora. Evo liste do sada pronađenih:

• IQGAP1 (Protein koji aktivira IQ domen GTP-aza): efektor RhoC za poboljšanje ekspresije ciklina E i ciklina D1. Ovo je rezultiralo promocijom ćelija da brže uđu u S fazu ^[17]
• ROCK-1 ^[13][18]
• MMP9: neophodno za regulaciju ECM ^[13]
• FMNL3: a Formin downstream target, which is used to regulate where Rac1 is active ^[16]
• MAPK put: regulacija VEGF-a, osnovnih fibroblastnih faktora rasta i ekspresije interleukina 6 i 8 ^[15][19]
• Notch1 ^[15]
• PI3K/AKt put: Proliferacija i invazivnost ^[15][20]
• Pyk2: metastaziranje ^[15][21]

Proučavani tipovi raka sa RhoC

Utvrđeno je da je RhoC prekomjerno izražen u:

• Rak pluća^[12]
• Rak želuca^[17]
• Rak jajnika^[13]
• Rak dojke^[19][22]
• Hepatočeklijski kancer ^[23]
• Rak gušterače^[13]
• Rak debelog crijeva^[24]
• Rak urogenitalnog sistema^[13]
• Melanom ^[13]
• Rak prostate^[21]
• Rak grlića maternice^[15]

Potencijalne terapije

RhoC-ova mala interferirajuća RNK (siRNK) korištena je u studijama za uspješno inhibiranje proliferacije nekih invazivnih karcinoma ^[17][24] RhoC se može koristiti kao biomarker za procjenu metastatskog potencijala tumora ^[22][25] Jedna studija je koristila "RhoC shRNK posredovanu rekombinantnim adenovirusom u tandemski povezanoj ekspresiji" za uspješno inhibiranje RhoC^[24] Utvrđeno je da ekspresija RhoC nije važna za embriogenezu, već je važna samo za metastaze, što bi ga činilo dobrom metom za liječenje.^[15] RhoC ciljana terapija (RV001 od RhoVac) trenutno se testira na raku prostate u tekućem programu kliničke faze 2b u SAD-u i Evropi. Rezultati se očekuju sredinom 2022. (Referenca: https://clinicaltrials.gov/ct2/show/NCT04114825)

Reference

1. GRCh38: Ensembl release 89: ENSG00000155366 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000002233 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ridley A. (2006). "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking". Trends Cell Biol. 16 (10): 522–9. doi:10.1016/j.tcb.2006.08.006. PMID 16949823.
6. "Entrez Gene: RHOC ras homolog gene family, member C".
7. "UniProt, P08134" (jezik: eng.). Pristupljeno 4. 12. 2021.
8. Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R (april 2010). "Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC". Oncogene. 29 (16): 2441–8. doi:10.1038/onc.2009.515. PMID 20101212.
9. Jaffe AB, Hall A (2005). "Rho GTPases: Biochemistry and Biology". Annual Review of Cell and Developmental Biology. 21: 247–69. doi:10.1146/annurev.cellbio.21.020604.150721. PMID 16212495.
10. Vega FM, Ridley AJ (2008). "Rho GTPases in Cancer Cell Biology". FEBS Letters. 582 (14): 2093–2101. doi:10.1016/j.febslet.2008.04.039. PMID 18460342.
11. Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I (juni 2003). "Up-Regulation of Small GTPases, RhoA and RhoC, Is Associated with Tumor Progression in Ovarian Carcinoma". Laboratory Investigation. 83 (6): 861–870. doi:10.1097/01.LAB.0000073128.16098.31. PMID 12808121. S2CID 22119772.
12. Ikoma T, Takahashi T, Nagano S, Li YM, Ohno Y, Ando K, Fujiwara T, Fujiwara H, Kosai K (februar 2004). "A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice". Clinical Cancer Research. 10 (3): 1192–1200. doi:10.1158/1078-0432.ccr-03-0275. PMID 14871999.
13. Zhao 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. PMID 20022093.
14. Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW (septembar 2005). "RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis". Genes Dev. 19 (17): 1974–9. doi:10.1101/gad.1310805. PMC 1199568. PMID 16107613.
15. Srivastava S, Ramdass B, Nagarajan S, Rehman M, Mukherjee G, Krishna S (2010). "Notch1 Regulates the Functional Contribution of RhoC to Cervical Carcinoma Progression". British Journal of Cancer. 102 (1): 196–205. doi:10.1038/sj.bjc.6605451. PMC 2813755. PMID 19953094.
16. Vega FM, Fruhwirth G, Ng T, Ridley AJ (2011). "RhoA and RhoC Have Distinct Roles in Migration and Invasion by Acting through Different Targets". The Journal of Cell Biology. 193 (4): 655–65. doi:10.1083/jcb.201011038. PMC 3166870. PMID 21576392.
17. Wu Y, Tao Y, Chen Y, Xu W (2012). "RhoC Regulates the Proliferation of Gastric Cancer Cells through Interaction with IQGAP1". PLOS ONE. 7 (11): e48917. doi:10.1371/journal.pone.0048917. PMC 3492142. PMID 23145020.
18. 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. PMID 10498656.
19. Van 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. PMID 12090470. S2CID 211284.
20. Sun HW, Tong SL, He J, Wang Q, Zou L, Ma SJ, Tan HY, Luo JF, Wu HX (2007). "RhoA and RhoC -siRNA Inhibit the Proliferation and Invasiveness Activity of Human Gastric Carcinoma by Rho/PI3K/Akt Pathway". World Journal of Gastroenterology. 13 (25): 3517–22. doi:10.3748/wjg.v13.i25.3517. PMC 4146790. PMID 17659701.
21. Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, Tsukada T, et al. (2008). "RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer". Cancer Research. 68 (18): 7613–20. doi:10.1158/0008-5472.CAN-07-6700. PMC 2741300. PMID 18794150.
22. Kleer 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. PMID 16187229. S2CID 9215922.
23. Wang W, Wu F, Fang F, Tao Y, Yang L (2008). "RhoC Is Essential for Angiogenesis Induced by Hepatocellular Carcinoma Cells via Regulation of Endothelial Cell Organization". Cancer Science. 99 (10): 2012–18. doi:10.1111/j.1349-7006.2008.00902.x. PMID 19016761.
24. Wang H, Zhao G, Liu X, Sui A, Yang K, Yao R, Wang Z, Shi Q (2010). "Silencing of RhoA and RhoC Expression by RNA Interference Suppresses Human Colorectal Carcinoma Growth in Vivo". Journal of Experimental & Clinical Cancer Research. 29: 123. doi:10.1186/1756-9966-29-123. PMC 2945978. PMID 20828398.
25. Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, Leung S, et al. (2008). "Ovarian Carcinoma Subtypes Are Different Diseases: Implications for Biomarker Studies". PLOS Medicine. 5 (12): e232. doi:10.1371/journal.pmed.0050232. PMC 2592352. PMID 19053170.

Dopunska literatura

• Adamson P, Paterson HF, Hall A (1992). "Intracellular localization of the P21rho proteins". J. Cell Biol. 119 (3): 617–27. doi:10.1083/jcb.119.3.617. PMC 2289677. PMID 1383236.
• Arthur WT, Ellerbroek SM, Der CJ, et al. (2003). "XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC". J. Biol. Chem. 277 (45): 42964–72. doi:10.1074/jbc.M207401200. PMID 12221096.
• Chardin P, Madaule P, Tavitian A (1988). "Coding sequence of human rho cDNAs clone 6 and clone 9". Nucleic Acids Res. 16 (6): 2717. doi:10.1093/nar/16.6.2717. PMC 336400. PMID 3283705.
• Clark EA, Golub TR, Lander ES, Hynes RO (2000). "Genomic analysis of metastasis reveals an essential role for RhoC". Nature. 406 (6795): 532–5. doi:10.1038/35020106. PMID 10952316. S2CID 4301092.
• Diviani D, Soderling J, Scott JD (2001). "AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation". J. Biol. Chem. 276 (47): 44247–57. doi:10.1074/jbc.M106629200. PMID 11546812.
• Kleer CG, van Golen KL, Zhang Y, et al. (2002). "Characterization of RhoC expression in benign and malignant breast disease: a potential new marker for small breast carcinomas with metastatic ability". Am. J. Pathol. 160 (2): 579–84. doi:10.1016/S0002-9440(10)64877-8. PMC 1850656. PMID 11839578.
• Madaule P, Axel R (1985). "A novel ras-related gene family". Cell. 41 (1): 31–40. doi:10.1016/0092-8674(85)90058-3. PMID 3888408. S2CID 32708060.
• 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. PMID 10436159.
• Reid T, Furuyashiki T, Ishizaki T, et al. (1996). "Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain". J. Biol. Chem. 271 (23): 13556–60. doi:10.1074/jbc.271.23.13556. PMID 8662891.
• Shao F, Dixon JE (2003). "YopT is a cysteine protease cleaving Rho family GTPases". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. 529: 79–84. doi:10.1007/0-306-48416-1_14. ISBN 0-306-47759-9. PMID 12756732.
• van Golen KL, Bao LW, Pan Q, et al. (2002). "Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer" (PDF). Clin. Exp. Metastasis. 19 (4): 301–11. doi:10.1023/A:1015518114931. hdl:2027.42/42584. PMID 12090470. S2CID 211284.
• Wheeler AP, Ridley AJ (2004). "Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility". Exp. Cell Res. 301 (1): 43–9. doi:10.1016/j.yexcr.2004.08.012. PMID 15501444.

Vanjski linkovi

• Laudanna C (2008). "RhoC". AfCS-Nature Molecule Pages. doi:10.1038/mp.a002065.01.
• "RhoC : Abstract : UCSD-Nature Molecule Pages". Arhivirano s originala, 4. 12. 2021. Pristupljeno 4. 12. 2021.

Šablon:Rho porodica GTPaza