RAC1

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RAC1
Protein RAC1 PDB 1ds6.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases RAC1, MIG5, Rac-1, TC-25, p21-Rac1, ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)
External IDs OMIM: 602048 MGI: 97845 HomoloGene: 69035 GeneCards: 5879
RNA expression pattern
PBB GE RAC1 208640 at tn.png

PBB GE RAC1 208641 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_198829
NM_006908
NM_018890

NM_009007

RefSeq (protein)

NP_008839.2
NP_061485.1

NP_033033.1

Location (UCSC) Chr 7: 6.37 – 6.4 Mb Chr 5: 143.5 – 143.53 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

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.[1][2] This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions.[3]

Function[edit]

Rac1 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. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of GLUT4[4][5] translocation to glucose uptake, cell growth, cytoskeletal reorganization, and the activation of protein kinases.[6]

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.[7] 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.[8] 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.[9] Such abnormal cell motility may result in epithelial mesenchymal transition (EMT) – a driving mechanism for tumor metastasis as well as drug-resistant tumor relapse.[10][11]

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.[12][13][5] 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 signaling 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[14][4] and muscle stretching[15]

Clinical significance[edit]

Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving melanoma [16][17][18] and non-small cell lung cancer.[19] As a result, Rac1 is considered a therapeutic target for many of these diseases.[20]

A few recent studies have also exploited targeted therapy to suppress tumor growth by pharmacological inhibition of Rac1 activity in metastatic melanoma and liver cancer as well as in human breast cancer.[21][22][23] For example, Rac1-dependent pathway inhibition resulted in the reversal of tumor cell phenotypes, suggesting Rac1 as a predictive marker and therapeutic target for trastuzumab-resistant breast cancer.[22] However, given Rac1's role in glucose transport, drugs that inhibits Rac1 could potentially be harmful to glucose homeostasis.

Interactions[edit]

RAC1 has been shown to interact with:

References[edit]

  1. ^ Didsbury J, Weber RF, Bokoch GM, Evans T, Snyderman R (Oct 1989). "rac, a novel ras-related family of proteins that are botulinum toxin substrates". The Journal of Biological Chemistry 264 (28): 16378–82. PMID 2674130. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. doi:10.1113/JP272039. ISSN 1469-7793. PMID 27061726. 
  5. ^ a b Ueda S, Kitazawa S, Ishida K, Nishikawa Y, Matsui M, Matsumoto H, Aoki T, Nozaki S, Takeda T, Tamori Y, Aiba A, Kahn CR, Kataoka T, Satoh T (Jul 2010). "Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma". FASEB Journal 24 (7): 2254–61. doi:10.1096/fj.09-137380. PMC 4183928. PMID 20203090. 
  6. ^ Ridley AJ (Oct 2006). "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking". Trends in Cell Biology 16 (10): 522–9. doi:10.1016/j.tcb.2006.08.006. PMID 16949823. 
  7. ^ Parri M, Chiarugi P (2010). "Rac and Rho GTPases in cancer cell motility control". Cell Communication and Signaling 8 (23): 23. doi:10.1186/1478-811x-8-23. 
  8. ^ Hanahan D, Weinberg RA (Mar 2011). "Hallmarks of cancer: the next generation". Cell 144 (5): 646–74. doi:10.1016/j.cell.2011.02.013. PMID 21376230. 
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  15. ^ Sylow L, Møller LL, Kleinert M, Richter EA, Jensen TE (Feb 2015). "Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1". The Journal of Physiology 593 (3): 645–56. doi:10.1113/jphysiol.2014.284281. PMC 4324711. PMID 25416624. 
  16. ^ Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (Jul 2012). "A landscape of driver mutations in melanoma". Cell 150 (2): 251–63. doi:10.1016/j.cell.2012.06.024. PMC 3600117. PMID 22817889. 
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  19. ^ Stallings-Mann ML, Waldmann J, Zhang Y, Miller E, Gauthier ML, Visscher DW, Downey GP, Radisky ES, Fields AP, Radisky DC (Jul 2012). "Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression". Science Translational Medicine 4 (142): 142ra95. doi:10.1126/scitranslmed.3004062. PMC 3733503. PMID 22786680. 
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Further reading[edit]

External links[edit]