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Aliases | RAC1, MIG5, Rac-1, TC-25, p21-Rac1, ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1), Rac family small GTPase 1, MRD48 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 602048; MGI: 97845; HomoloGene: 69035; GeneCards: RAC1; OMA:RAC1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is a protein found in human cells. It is encoded by the RAC1 gene.[5][6] This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions.[7]
Function
[edit]Rac1 is a small (~21 kDa) signalling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of GLUT4[8][9] translocation to glucose uptake, cell growth, cytoskeletal reorganization, antimicrobial cytotoxicity,[10] and the activation of protein kinases.[11]
Rac1 is a pleiotropic regulator of many cellular processes, including the cell cycle, cell-cell adhesion, motility (through the actin network), and of epithelial differentiation (proposed to be necessary for maintaining epidermal stem cells).
Role in cancer
[edit]Along with other subfamily of Rac and Rho proteins, they exert an important regulatory role specifically in cell motility and cell growth. Rac1 has ubiquitous tissue expression, and drives cell motility by formation of lamellipodia.[12] In order for cancer cells to grow and invade local and distant tissues, deregulation of cell motility is one of the hallmark events in cancer cell invasion and metastasis.[13] Overexpression of a constitutively active Rac1 V12 in mice caused a tumour that is phenotypically indistinguishable from human Kaposi's sarcoma.[14] Activating or gain-of-function mutations of Rac1 are shown to play active roles in promoting mesenchymal-type of cell movement assisted by NEDD9 and DOCK3 protein complex.[15] Such abnormal cell motility may result in epithelial mesenchymal transition (EMT) – a driving mechanism for tumour metastasis as well as drug-resistant tumour relapse.[16][17]
Role in glucose transport
[edit]Rac1 is expressed in significant amounts in insulin sensitive tissues, such as adipose tissue and skeletal muscle. Here Rac1 regulated the translocation of glucose transporting GLUT4 vesicles from intracellular compartments to the plasma membrane.[9][18][19] In response to insulin, this allows for blood glucose to enter the cell to lower blood glucose. In conditions of obesity and type 2 diabetes, Rac1 signalling in skeletal muscle is dysfunctional, suggesting that Rac1 contributes to the progression of the disease. Rac1 protein is also necessary for glucose uptake in skeletal muscle activated by exercise[8][20] and muscle stretching[21]
Clinical significance
[edit]Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving melanoma[22][23][24] and non-small cell lung cancer.[25] As a result, Rac1 is considered a therapeutic target for many of these diseases.[26]
A few recent studies have also exploited targeted therapy to suppress tumour growth by pharmacological inhibition of Rac1 activity in metastatic melanoma and liver cancer as well as in human breast cancer.[27][28][29] For example, Rac1-dependent pathway inhibition resulted in the reversal of tumour cell phenotypes, suggesting Rac1 as a predictive marker and therapeutic target for trastuzumab-resistant breast cancer.[28] However, given Rac1's role in glucose transport, drugs that inhibit Rac1 could potentially be harmful to glucose homeostasis.
Dominant negative or constitutively active germline RAC1 mutations cause diverse phenotypes that have been grouped together as Mental Retardation Type 48.[30] Most mutations cause microcephaly while some specific changes appear to result in macrocephaly.
Interactions
[edit]RAC1 has been shown to interact with:
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000136238 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001847 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ Jordan P, Brazåo R, Boavida MG, Gespach C, Chastre E (Nov 1999). "Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors". Oncogene. 18 (48): 6835–9. doi:10.1038/sj.onc.1203233. PMID 10597294.
- ^ Zhou C, Licciulli S, Avila JL, Cho M, Troutman S, Jiang P, Kossenkov AV, Showe LC, Liu Q, Vachani A, Albelda SM, Kissil JL (Feb 2013). "The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis". Oncogene. 32 (7): 903–9. doi:10.1038/onc.2012.99. PMC 3384754. PMID 22430205.
- ^ a b Sylow, Lykke; Nielsen, Ida L.; Kleinert, Maximilian; Møller, Lisbeth L. V.; Ploug, Thorkil; Schjerling, Peter; Bilan, Philip J.; Klip, Amira; Jensen, Thomas E. (2016-04-09). "Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice". The Journal of Physiology. 594 (17): 4997–5008. doi:10.1113/JP272039. ISSN 1469-7793. PMC 5009787. PMID 27061726.
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- ^ Xiang RF (Mar 2016). "Ras-related C3 Botulinum Toxin Substrate (Rac) and Src Family Kinases (SFK) Are Proximal and Essential for Phosphatidylinositol 3-Kinase (PI3K) Activation in Natural Killer (NK) Cell-mediated Direct Cytotoxicity against Cryptococcus neoformans". J Biol Chem. 291 (13): 6912–22. doi:10.1074/jbc.M115.681544. PMC 4807276. PMID 26867574.
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- ^ Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R (Sep 2012). "Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma". Nature Genetics. 44 (9): 1006–14. doi:10.1038/ng.2359. PMC 3432702. PMID 22842228.
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- ^ Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ, et al. (Nov 2011). "Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs". International Journal of Molecular Medicine. 28 (5): 769–776. doi:10.3892/ijmm.2011.775. PMID 21837360.
- ^ a b Dokmanovic M, Hirsch DS, Shen Y, Wu WJ (Jun 2009). "Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer". Molecular Cancer Therapeutics. 8 (6): 1557–69. doi:10.1158/1535-7163.mct-09-0140. PMID 19509242.
- ^ Liu S, Yu M, He Y, Xiao L, Wang F, Song C, Sun S, Ling C, Xu Z (Jun 2008). "Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway". Hepatology. 47 (6): 1964–73. doi:10.1002/hep.22240. PMID 18506888. S2CID 21106205.
- ^ Reijnders, Margot R.F.; Ansor, Nurhuda M.; Kousi, Maria; Yue, Wyatt W.; Tan, Perciliz L.; Clarkson, Katie; Clayton-Smith, Jill; Corning, Ken; Jones, Julie R.; Lam, Wayne W.K.; Mancini, Grazia M.S.; Marcelis, Carlo; Mohammed, Shehla; Pfundt, Rolph; Roifman, Maian; Cohn, Ronald; Chitayat, David; Millard, Tom H.; Katsanis, Nicholas; Brunner, Han G.; Banka, Siddharth (September 2017). "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes". The American Journal of Human Genetics. 101 (3): 466–477. doi:10.1016/j.ajhg.2017.08.007. PMC 5591022. PMID 28886345.
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- ^ Van Aelst L, Joneson T, Bar-Sagi D (Aug 1996). "Identification of a novel Rac1-interacting protein involved in membrane ruffling". The EMBO Journal. 15 (15): 3778–86. doi:10.1002/j.1460-2075.1996.tb00751.x. PMC 452058. PMID 8670882.
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- ^ Westendorf JJ (Dec 2001). "The formin/diaphanous-related protein, FHOS, interacts with Rac1 and activates transcription from the serum response element". The Journal of Biological Chemistry. 276 (49): 46453–9. doi:10.1074/jbc.M105162200. PMID 11590143.
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- ^ a b Zhang B, Chernoff J, Zheng Y (Apr 1998). "Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA". The Journal of Biological Chemistry. 273 (15): 8776–82. doi:10.1074/jbc.273.15.8776. PMID 9535855.
- ^ Kuroda S, Fukata M, Kobayashi K, Nakafuku M, Nomura N, Iwamatsu A, Kaibuchi K (Sep 1996). "Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1". The Journal of Biological Chemistry. 271 (38): 23363–7. doi:10.1074/jbc.271.38.23363. PMID 8798539.
- ^ Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, Matsuura Y, Iwamatsu A, Perez F, Kaibuchi K (Jun 2002). "Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170". Cell. 109 (7): 873–85. doi:10.1016/S0092-8674(02)00800-0. PMID 12110184. S2CID 15158637.
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- ^ a b Noda Y, Takeya R, Ohno S, Naito S, Ito T, Sumimoto H (Feb 2001). "Human homologues of the Caenorhabditis elegans cell polarity protein PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to atypical protein kinase C". Genes to Cells. 6 (2): 107–19. doi:10.1046/j.1365-2443.2001.00404.x. PMID 11260256. S2CID 8789941.
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- ^ Zhao C, Ma H, Bossy-Wetzel E, Lipton SA, Zhang Z, Feng GS (Sep 2003). "GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2". The Journal of Biological Chemistry. 278 (36): 34641–53. doi:10.1074/jbc.M304594200. PMID 12819203.
- ^ Moon SY, Zang H, Zheng Y (Feb 2003). "Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP". The Journal of Biological Chemistry. 278 (6): 4151–9. doi:10.1074/jbc.M207789200. PMID 12454018.
- ^ Simon AR, Vikis HG, Stewart S, Fanburg BL, Cochran BH, Guan KL (Oct 2000). "Regulation of STAT3 by direct binding to the Rac1 GTPase". Science. 290 (5489): 144–7. Bibcode:2000Sci...290..144S. doi:10.1126/science.290.5489.144. PMID 11021801.
- ^ Worthylake DK, Rossman KL, Sondek J (Dec 2000). "Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1". Nature. 408 (6813): 682–8. Bibcode:2000Natur.408..682W. doi:10.1038/35047014. PMID 11130063. S2CID 4429919.
- ^ Gao Y, Xing J, Streuli M, Leto TL, Zheng Y (Dec 2001). "Trp(56) of rac1 specifies interaction with a subset of guanine nucleotide exchange factors". The Journal of Biological Chemistry. 276 (50): 47530–41. doi:10.1074/jbc.M108865200. PMID 11595749.
Further reading
[edit]- Benitah SA, Frye M, Glogauer M, Watt FM (Aug 2005). "Stem cell depletion through epidermal deletion of Rac1". Science. 309 (5736): 933–5. Bibcode:2005Sci...309..933A. doi:10.1126/science.1113579. PMID 16081735. S2CID 21888612.
- Ramakers GJ (Apr 2002). "Rho proteins, mental retardation and the cellular basis of cognition". Trends in Neurosciences. 25 (4): 191–9. doi:10.1016/S0166-2236(00)02118-4. PMID 11998687. S2CID 13941716.
- Esufali S, Charames GS, Bapat B (Oct 2007). "Suppression of nuclear Wnt signaling leads to stabilization of Rac1 isoforms". FEBS Letters. 581 (25): 4850–6. doi:10.1016/j.febslet.2007.09.013. PMID 17888911. S2CID 1457000.
External links
[edit]- rac1+GTP-Binding+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- RAC1 Info with links in the Cell Migration Gateway Archived 2014-12-11 at the Wayback Machine