Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is a
protein found in human cells. It is encoded by the RAC1gene.[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
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
epithelialdifferentiation (proposed to be necessary for maintaining epidermal stem cells).
Role in cancer
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
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
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.
^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.
PMID16949823.
^Yang WH, Lan HY, Huang CH, Tai SK, Tzeng CH, Kao SY, Wu KJ, Hung MC, Yang MH (Apr 2012). "RAC1 activation mediates Twist1-induced cancer cell migration". Nature Cell Biology. 14 (4): 366–74.
doi:
10.1038/ncb2455.
PMID22407364.
S2CID4755216.
^Sylow L, Kleinert M, Pehmøller C, Prats C, Chiu TT, Klip A, Richter EA, Jensen TE (Feb 2014). "Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance". Cellular Signalling. 26 (2): 323–31.
doi:
10.1016/j.cellsig.2013.11.007.
PMID24216610.
^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.
PMC3600117.
PMID22817889.
^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.
PMC3432702.
PMID22842228.
^Tarricone C, Xiao B, Justin N, Walker PA, Rittinger K, Gamblin SJ, Smerdon SJ (May 2001). "The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways". Nature. 411 (6834): 215–9.
doi:
10.1038/35075620.
PMID11346801.
S2CID4324211.
^Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007).
"Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89.
doi:
10.1038/msb4100134.
PMC1847948.
PMID17353931.
^Grizot S, Fauré J, Fieschi F, Vignais PV, Dagher MC, Pebay-Peyroula E (Aug 2001). "Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation". Biochemistry. 40 (34): 10007–13.
doi:
10.1021/bi010288k.
PMID11513578.
^Gorvel JP, Chang TC, Boretto J, Azuma T, Chavrier P (Jan 1998). "Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity". FEBS Letters. 422 (2): 269–73.
doi:
10.1016/S0014-5793(98)00020-9.
PMID9490022.
S2CID10817327.
^Di-Poï N, Fauré J, Grizot S, Molnár G, Pick E, Dagher MC (Aug 2001). "Mechanism of NADPH oxidase activation by the Rac/Rho-GDI complex". Biochemistry. 40 (34): 10014–22.
doi:
10.1021/bi010289c.
PMID11513579.
^Fauré J, Dagher MC (May 2001). "Interactions between Rho GTPases and Rho GDP dissociation inhibitor (Rho-GDI)". Biochimie. 83 (5): 409–14.
doi:
10.1016/S0300-9084(01)01263-9.
PMID11368848.
Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is a
protein found in human cells. It is encoded by the RAC1gene.[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
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
epithelialdifferentiation (proposed to be necessary for maintaining epidermal stem cells).
Role in cancer
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
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
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.
^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.
PMID16949823.
^Yang WH, Lan HY, Huang CH, Tai SK, Tzeng CH, Kao SY, Wu KJ, Hung MC, Yang MH (Apr 2012). "RAC1 activation mediates Twist1-induced cancer cell migration". Nature Cell Biology. 14 (4): 366–74.
doi:
10.1038/ncb2455.
PMID22407364.
S2CID4755216.
^Sylow L, Kleinert M, Pehmøller C, Prats C, Chiu TT, Klip A, Richter EA, Jensen TE (Feb 2014). "Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance". Cellular Signalling. 26 (2): 323–31.
doi:
10.1016/j.cellsig.2013.11.007.
PMID24216610.
^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.
PMC3600117.
PMID22817889.
^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.
PMC3432702.
PMID22842228.
^Tarricone C, Xiao B, Justin N, Walker PA, Rittinger K, Gamblin SJ, Smerdon SJ (May 2001). "The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways". Nature. 411 (6834): 215–9.
doi:
10.1038/35075620.
PMID11346801.
S2CID4324211.
^Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007).
"Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89.
doi:
10.1038/msb4100134.
PMC1847948.
PMID17353931.
^Grizot S, Fauré J, Fieschi F, Vignais PV, Dagher MC, Pebay-Peyroula E (Aug 2001). "Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation". Biochemistry. 40 (34): 10007–13.
doi:
10.1021/bi010288k.
PMID11513578.
^Gorvel JP, Chang TC, Boretto J, Azuma T, Chavrier P (Jan 1998). "Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity". FEBS Letters. 422 (2): 269–73.
doi:
10.1016/S0014-5793(98)00020-9.
PMID9490022.
S2CID10817327.
^Di-Poï N, Fauré J, Grizot S, Molnár G, Pick E, Dagher MC (Aug 2001). "Mechanism of NADPH oxidase activation by the Rac/Rho-GDI complex". Biochemistry. 40 (34): 10014–22.
doi:
10.1021/bi010289c.
PMID11513579.
^Fauré J, Dagher MC (May 2001). "Interactions between Rho GTPases and Rho GDP dissociation inhibitor (Rho-GDI)". Biochimie. 83 (5): 409–14.
doi:
10.1016/S0300-9084(01)01263-9.
PMID11368848.