RAC1: Difference between revisions

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== Function ==
== Function ==


Rac1 is a small (~21 kDa) signaling [[G protein]] (more specifically a [[GTPase]]), and is a member of the [[Rac protein|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]]<ref name=":0">{{Cite journal|last=Sylow|first=Lykke|last2=Nielsen|first2=Ida L.|last3=Kleinert|first3=Maximilian|last4=Møller|first4=Lisbeth L. V.|last5=Ploug|first5=Thorkil|last6=Schjerling|first6=Peter|last7=Bilan|first7=Philip J.|last8=Klip|first8=Amira|last9=Jensen|first9=Thomas E.|date=2016-04-09|title=Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice|journal=The Journal of Physiology|doi=10.1113/JP272039|issn=1469-7793|pmid=27061726}}</ref><ref name=":1" /> translocation to glucose uptake, [[cell growth]], [[cytoskeleton|cytoskeletal]] reorganization, antimicrobial cytotoxicity,<ref name="pmid26867574">{{cite journal | vauthors = Xiang RF | title = 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 | journal = J Biol Chem | volume = 291 | issue = 13 | pages = 6912–22 | date = Mar 2016 | pmid = 26867574 | doi = 10.1074/jbc.M115.681544 | pmc=4807276}}</ref> and the activation of protein [[kinase]]s.<ref name="pmid16949823">{{cite journal | vauthors = Ridley AJ | title = Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking | journal = Trends in Cell Biology | volume = 16 | issue = 10 | pages = 522–9 | date = Oct 2006 | pmid = 16949823 | doi = 10.1016/j.tcb.2006.08.006 }}</ref>
Rac1 is a small (~21 kDa) signaling [[G protein]] (more specifically a [[GTPase]]), and is a member of the [[Rac protein|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]]<ref name=":0">{{Cite journal|last=Sylow|first=Lykke|last2=Nielsen|first2=Ida L.|last3=Kleinert|first3=Maximilian|last4=Møller|first4=Lisbeth L. V.|last5=Ploug|first5=Thorkil|last6=Schjerling|first6=Peter|last7=Bilan|first7=Philip J.|last8=Klip|first8=Amira|last9=Jensen|first9=Thomas E.|date=2016-04-09|title=Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice|journal=The Journal of Physiology|volume=594|issue=17|pages=4997–5008|doi=10.1113/JP272039|issn=1469-7793|pmid=27061726|pmc=5009787}}</ref><ref name=":1" /> translocation to glucose uptake, [[cell growth]], [[cytoskeleton|cytoskeletal]] reorganization, antimicrobial cytotoxicity,<ref name="pmid26867574">{{cite journal | vauthors = Xiang RF | title = 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 | journal = J Biol Chem | volume = 291 | issue = 13 | pages = 6912–22 | date = Mar 2016 | pmid = 26867574 | doi = 10.1074/jbc.M115.681544 | pmc=4807276}}</ref> and the activation of protein [[kinase]]s.<ref name="pmid16949823">{{cite journal | vauthors = Ridley AJ | title = Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking | journal = Trends in Cell Biology | volume = 16 | issue = 10 | pages = 522–9 | date = Oct 2006 | pmid = 16949823 | doi = 10.1016/j.tcb.2006.08.006 }}</ref>


Rac1 is a [[pleiotropic]] regulator of many cellular processes, including the cell cycle, cell-cell adhesion, [[motility]] (through the actin network), and of [[epithelial]] [[cellular differentiation|differentiation]] (proposed to be necessary for maintaining epidermal stem cells).
Rac1 is a [[pleiotropic]] regulator of many cellular processes, including the cell cycle, cell-cell adhesion, [[motility]] (through the actin network), and of [[epithelial]] [[cellular differentiation|differentiation]] (proposed to be necessary for maintaining epidermal stem cells).
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== Role in cancer ==
== 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]].<ref name="parri">{{cite journal | vauthors = Parri M, Chiarugi P | title = Rac and Rho GTPases in cancer cell motility control | journal = Cell Communication and Signaling | volume = 8 | issue = 23 | pages = 23 | date = 2010 | pmid =  | doi = 10.1186/1478-811x-8-23 }}</ref> 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.<ref name="hallmarks">{{cite journal | vauthors = Hanahan D, Weinberg RA | title = Hallmarks of cancer: the next generation | journal = Cell | volume = 144 | issue = 5 | pages = 646–74 | date = Mar 2011 | pmid = 21376230 | doi = 10.1016/j.cell.2011.02.013 }}</ref> Overexpression of a constitutively active Rac1 V12 in mice caused a tumor that's phenotypically indistinguishable form human Kaposi's sarcoma.<ref>{{Cite journal|last=Ma|first=Qi|last2=Cavallin|first2=Lucas E.|last3=Yan|first3=Bin|last4=Zhu|first4=Shoukang|last5=Duran|first5=Elda Margarita|last6=Wang|first6=Huili|last7=Hale|first7=Laura P.|last8=Dong|first8=Chunming|last9=Cesarman|first9=Ethel|date=2009-05-26|title=Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma|url=http://www.pnas.org/content/106/21/8683|journal=Proceedings of the National Academy of Sciences|language=en|volume=106|issue=21|pages=8683–8688|doi=10.1073/pnas.0812688106|issn=0027-8424|pmc=2679580|pmid=19429708}}</ref> 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.<ref name="sanz">{{cite journal | vauthors = Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P, Pinner S, Sahai E, Marshall CJ | title = Rac activation and inactivation control plasticity of tumor cell movement | journal = Cell | volume = 135 | issue = 3 | pages = 510–23 | date = Oct 2008 | pmid = 18984162 | doi = 10.1016/j.cell.2008.09.043 }}</ref> Such abnormal cell motility may result in [[epithelial mesenchymal transition]] (EMT) – a driving mechanism for tumor metastasis as well as drug-resistant tumor relapse.<ref name="stallmann">{{cite journal  |vauthors=Stallings-Mann ML, Waldmann J, Zhang Y, Miller E, Gauthier ML, Visscher DW, etal | title = Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression. | journal = Science translational medicine. | volume = 4 | issue = 142 | pages = 510–523 |date=Jul 11, 2012 | pmid = | doi = | url =  }}</ref><ref name="yang">{{cite journal | vauthors = Yang WH, Lan HY, Huang CH, Tai SK, Tzeng CH, Kao SY, Wu KJ, Hung MC, Yang MH | title = RAC1 activation mediates Twist1-induced cancer cell migration | journal = Nature Cell Biology | volume = 14 | issue = 4 | pages = 366–74 | date = Apr 2012 | pmid =  22407364| doi = 10.1038/ncb2455 }}</ref>
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]].<ref name="parri">{{cite journal | vauthors = Parri M, Chiarugi P | title = Rac and Rho GTPases in cancer cell motility control | journal = Cell Communication and Signaling | volume = 8 | issue = 23 | pages = 23 | date = 2010 | pmid =  20822528| pmc = 2941746 | doi = 10.1186/1478-811x-8-23 }}</ref> 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.<ref name="hallmarks">{{cite journal | vauthors = Hanahan D, Weinberg RA | title = Hallmarks of cancer: the next generation | journal = Cell | volume = 144 | issue = 5 | pages = 646–74 | date = Mar 2011 | pmid = 21376230 | doi = 10.1016/j.cell.2011.02.013 }}</ref> Overexpression of a constitutively active Rac1 V12 in mice caused a tumor that's phenotypically indistinguishable from human Kaposi's sarcoma.<ref>{{Cite journal|last=Ma|first=Qi|last2=Cavallin|first2=Lucas E.|last3=Yan|first3=Bin|last4=Zhu|first4=Shoukang|last5=Duran|first5=Elda Margarita|last6=Wang|first6=Huili|last7=Hale|first7=Laura P.|last8=Dong|first8=Chunming|last9=Cesarman|first9=Ethel|date=2009-05-26|title=Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma|url=http://www.pnas.org/content/106/21/8683|journal=Proceedings of the National Academy of Sciences|language=en|volume=106|issue=21|pages=8683–8688|doi=10.1073/pnas.0812688106|issn=0027-8424|pmc=2679580|pmid=19429708}}</ref> 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.<ref name="sanz">{{cite journal | vauthors = Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P, Pinner S, Sahai E, Marshall CJ | title = Rac activation and inactivation control plasticity of tumor cell movement | journal = Cell | volume = 135 | issue = 3 | pages = 510–23 | date = Oct 2008 | pmid = 18984162 | doi = 10.1016/j.cell.2008.09.043 }}</ref> Such abnormal cell motility may result in [[epithelial mesenchymal transition]] (EMT) – a driving mechanism for tumor metastasis as well as drug-resistant tumor relapse.<ref name="stallmann">{{cite journal  |vauthors=Stallings-Mann ML, Waldmann J, Zhang Y, Miller E, Gauthier ML, Visscher DW, etal | title = Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression | journal = Science Translational Medicine | volume = 4 | issue = 142 | pages = 510–523 |date=Jul 11, 2012 | pmid = | doi = | url =  }}</ref><ref name="yang">{{cite journal | vauthors = Yang WH, Lan HY, Huang CH, Tai SK, Tzeng CH, Kao SY, Wu KJ, Hung MC, Yang MH | title = RAC1 activation mediates Twist1-induced cancer cell migration | journal = Nature Cell Biology | volume = 14 | issue = 4 | pages = 366–74 | date = Apr 2012 | pmid =  22407364| doi = 10.1038/ncb2455 }}</ref>


== Role in glucose transport==
== Role in glucose transport==
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Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving [[melanoma]] <ref name="pmid22817889">{{cite journal | vauthors = 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 | title = A landscape of driver mutations in melanoma | journal = Cell | volume = 150 | issue = 2 | pages = 251–63 | date = Jul 2012 | pmid = 22817889 | pmc = 3600117 | doi = 10.1016/j.cell.2012.06.024 }}</ref><ref name="pmid22842228">{{cite journal | vauthors = 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 | title = Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma | journal = Nature Genetics | volume = 44 | issue = 9 | pages = 1006–14 | date = Sep 2012 | pmid = 22842228 | pmc = 3432702 | doi = 10.1038/ng.2359 }}</ref><ref name="pmid17904119">{{cite journal | vauthors = Bauer NN, Chen YW, Samant RS, Shevde LA, Fodstad O | title = Rac1 activity regulates proliferation of aggressive metastatic melanoma | journal = Experimental Cell Research | volume = 313 | issue = 18 | pages = 3832–9 | date = Nov 2007 | pmid = 17904119 | doi = 10.1016/j.yexcr.2007.08.017 }}</ref> and [[non-small cell lung cancer]].<ref name="pmid22786680">{{cite journal | vauthors = Stallings-Mann ML, Waldmann J, Zhang Y, Miller E, Gauthier ML, Visscher DW, Downey GP, Radisky ES, Fields AP, Radisky DC | title = Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression | journal = Science Translational Medicine | volume = 4 | issue = 142 | pages = 142ra95 | date = Jul 2012 | pmid = 22786680 | pmc = 3733503 | doi = 10.1126/scitranslmed.3004062 }}</ref> As a result, Rac1 is considered a therapeutic target for many of these diseases.<ref name="pmid22786678">{{cite journal | vauthors = McAllister SS | title = Got a light? Illuminating lung cancer | journal = Science Translational Medicine | volume = 4 | issue = 142 | pages = 142fs22 | date = Jul 2012 | pmid = 22786678 | doi = 10.1126/scitranslmed.3004446 }}</ref>
Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving [[melanoma]] <ref name="pmid22817889">{{cite journal | vauthors = 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 | title = A landscape of driver mutations in melanoma | journal = Cell | volume = 150 | issue = 2 | pages = 251–63 | date = Jul 2012 | pmid = 22817889 | pmc = 3600117 | doi = 10.1016/j.cell.2012.06.024 }}</ref><ref name="pmid22842228">{{cite journal | vauthors = 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 | title = Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma | journal = Nature Genetics | volume = 44 | issue = 9 | pages = 1006–14 | date = Sep 2012 | pmid = 22842228 | pmc = 3432702 | doi = 10.1038/ng.2359 }}</ref><ref name="pmid17904119">{{cite journal | vauthors = Bauer NN, Chen YW, Samant RS, Shevde LA, Fodstad O | title = Rac1 activity regulates proliferation of aggressive metastatic melanoma | journal = Experimental Cell Research | volume = 313 | issue = 18 | pages = 3832–9 | date = Nov 2007 | pmid = 17904119 | doi = 10.1016/j.yexcr.2007.08.017 }}</ref> and [[non-small cell lung cancer]].<ref name="pmid22786680">{{cite journal | vauthors = Stallings-Mann ML, Waldmann J, Zhang Y, Miller E, Gauthier ML, Visscher DW, Downey GP, Radisky ES, Fields AP, Radisky DC | title = Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression | journal = Science Translational Medicine | volume = 4 | issue = 142 | pages = 142ra95 | date = Jul 2012 | pmid = 22786680 | pmc = 3733503 | doi = 10.1126/scitranslmed.3004062 }}</ref> As a result, Rac1 is considered a therapeutic target for many of these diseases.<ref name="pmid22786678">{{cite journal | vauthors = McAllister SS | title = Got a light? Illuminating lung cancer | journal = Science Translational Medicine | volume = 4 | issue = 142 | pages = 142fs22 | date = Jul 2012 | pmid = 22786678 | doi = 10.1126/scitranslmed.3004446 }}</ref>


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.<ref name="chen">{{cite journal  |vauthors=Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ, etal | title = Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs. | journal = International journal of molecular medicine| volume = 28 | issue = 5 | pages = 769–776 |date=Nov 2011 | pmid = | doi = | url =  }}</ref><ref name="dok">{{cite journal | vauthors = Dokmanovic M, Hirsch DS, Shen Y, Wu WJ | title = Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer | journal = Molecular Cancer Therapeutics | volume = 8 | issue = 6 | pages = 1557–69 | date = Jun 2009 | pmid =  | doi = 10.1158/1535-7163.mct-09-0140 }}</ref><ref name="liu">{{cite journal | vauthors = Liu S, Yu M, He Y, Xiao L, Wang F, Song C, Sun S, Ling C, Xu Z | title = Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway | journal = Hepatology | volume = 47 | issue = 6 | pages = 1964–73 | date = Jun 2008 | pmid =  18506888| doi = 10.1002/hep.22240 }}</ref>
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.<ref name="chen">{{cite journal  |vauthors=Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ, etal | title = Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs | journal = International Journal of Molecular Medicine| volume = 28 | issue = 5 | pages = 769–776 |date=Nov 2011 | pmid = | doi = | url =  }}</ref><ref name="dok">{{cite journal | vauthors = Dokmanovic M, Hirsch DS, Shen Y, Wu WJ | title = Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer | journal = Molecular Cancer Therapeutics | volume = 8 | issue = 6 | pages = 1557–69 | date = Jun 2009 | pmid =  19509242| doi = 10.1158/1535-7163.mct-09-0140 }}</ref><ref name="liu">{{cite journal | vauthors = Liu S, Yu M, He Y, Xiao L, Wang F, Song C, Sun S, Ling C, Xu Z | title = Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway | journal = Hepatology | volume = 47 | issue = 6 | pages = 1964–73 | date = Jun 2008 | pmid =  18506888| doi = 10.1002/hep.22240 }}</ref>
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.<ref name="dok"/> However, given Rac1's role in glucose transport, drugs that inhibits Rac1 could potentially be harmful to glucose homeostasis.
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.<ref name="dok"/> However, given Rac1's role in glucose transport, drugs that inhibits 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 [https://omim.org/entry/617751 Mental Retardation Type 48] <ref>{{cite journal|last1=Reijnders|first1=Margot R.F.|last2=Ansor|first2=Nurhuda M.|last3=Kousi|first3=Maria|last4=Yue|first4=Wyatt W.|last5=Tan|first5=Perciliz L.|last6=Clarkson|first6=Katie|last7=Clayton-Smith|first7=Jill|last8=Corning|first8=Ken|last9=Jones|first9=Julie R.|last10=Lam|first10=Wayne W.K.|last11=Mancini|first11=Grazia M.S.|last12=Marcelis|first12=Carlo|last13=Mohammed|first13=Shehla|last14=Pfundt|first14=Rolph|last15=Roifman|first15=Maian|last16=Cohn|first16=Ronald|last17=Chitayat|first17=David|last18=Millard|first18=Tom H.|last19=Katsanis|first19=Nicholas|last20=Brunner|first20=Han G.|last21=Banka|first21=Siddharth|title=RAC1  Missense Mutations in Developmental Disorders with Diverse Phenotypes|journal=The American Journal of Human Genetics|date=September 2017|volume=101|issue=3|pages=466–477|doi=10.1016/j.ajhg.2017.08.007}}</ref>. Most [[mutations]] cause [[microcephaly]] while some specific changes appear to result in [[macrocephaly]].
[[Dominant negative]] or [[Gene expression|constitutively active]] [[germline]] RAC1 mutations cause diverse [[phenotypes]] that have been grouped together as [https://omim.org/entry/617751 Mental Retardation Type 48].<ref>{{cite journal|last1=Reijnders|first1=Margot R.F.|last2=Ansor|first2=Nurhuda M.|last3=Kousi|first3=Maria|last4=Yue|first4=Wyatt W.|last5=Tan|first5=Perciliz L.|last6=Clarkson|first6=Katie|last7=Clayton-Smith|first7=Jill|last8=Corning|first8=Ken|last9=Jones|first9=Julie R.|last10=Lam|first10=Wayne W.K.|last11=Mancini|first11=Grazia M.S.|last12=Marcelis|first12=Carlo|last13=Mohammed|first13=Shehla|last14=Pfundt|first14=Rolph|last15=Roifman|first15=Maian|last16=Cohn|first16=Ronald|last17=Chitayat|first17=David|last18=Millard|first18=Tom H.|last19=Katsanis|first19=Nicholas|last20=Brunner|first20=Han G.|last21=Banka|first21=Siddharth|title=RAC1  Missense Mutations in Developmental Disorders with Diverse Phenotypes|journal=The American Journal of Human Genetics|date=September 2017|volume=101|issue=3|pages=466–477|doi=10.1016/j.ajhg.2017.08.007|pmid=28886345|pmc=5591022}}</ref> Most [[mutations]] cause [[microcephaly]] while some specific changes appear to result in [[macrocephaly]].


== Interactions ==
== Interactions ==
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* [[IQGAP1]],<ref name = pmid9535855/><ref name = pmid8798539>{{cite journal | vauthors = Kuroda S, Fukata M, Kobayashi K, Nakafuku M, Nomura N, Iwamatsu A, Kaibuchi K | title = Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 38 | pages = 23363–7 | date = Sep 1996 | pmid = 8798539 | doi = 10.1074/jbc.271.38.23363 }}</ref><ref name = pmid12110184>{{cite journal | vauthors = Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, Matsuura Y, Iwamatsu A, Perez F, Kaibuchi K | title = Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170 | journal = Cell | volume = 109 | issue = 7 | pages = 873–85 | date = Jun 2002 | pmid = 12110184 | doi = 10.1016/S0092-8674(02)00800-0 }}</ref><ref name = pmid8670801>{{cite journal | vauthors = Hart MJ, Callow MG, Souza B, Polakis P | title = IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs | journal = The EMBO Journal | volume = 15 | issue = 12 | pages = 2997–3005 | date = Jun 1996 | pmid = 8670801 | pmc = 450241 | doi =  }}</ref>
* [[IQGAP1]],<ref name = pmid9535855/><ref name = pmid8798539>{{cite journal | vauthors = Kuroda S, Fukata M, Kobayashi K, Nakafuku M, Nomura N, Iwamatsu A, Kaibuchi K | title = Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 38 | pages = 23363–7 | date = Sep 1996 | pmid = 8798539 | doi = 10.1074/jbc.271.38.23363 }}</ref><ref name = pmid12110184>{{cite journal | vauthors = Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, Matsuura Y, Iwamatsu A, Perez F, Kaibuchi K | title = Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170 | journal = Cell | volume = 109 | issue = 7 | pages = 873–85 | date = Jun 2002 | pmid = 12110184 | doi = 10.1016/S0092-8674(02)00800-0 }}</ref><ref name = pmid8670801>{{cite journal | vauthors = Hart MJ, Callow MG, Souza B, Polakis P | title = IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs | journal = The EMBO Journal | volume = 15 | issue = 12 | pages = 2997–3005 | date = Jun 1996 | pmid = 8670801 | pmc = 450241 | doi =  }}</ref>
* [[IQGAP2]],<ref name = pmid8756646>{{cite journal | vauthors = Brill S, Li S, Lyman CW, Church DM, Wasmuth JJ, Weissbach L, Bernards A, Snijders AJ | title = The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases | journal = Molecular and Cellular Biology | volume = 16 | issue = 9 | pages = 4869–78 | date = Sep 1996 | pmid = 8756646 | pmc = 231489 | doi =  10.1128/mcb.16.9.4869}}</ref>
* [[IQGAP2]],<ref name = pmid8756646>{{cite journal | vauthors = Brill S, Li S, Lyman CW, Church DM, Wasmuth JJ, Weissbach L, Bernards A, Snijders AJ | title = The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases | journal = Molecular and Cellular Biology | volume = 16 | issue = 9 | pages = 4869–78 | date = Sep 1996 | pmid = 8756646 | pmc = 231489 | doi =  10.1128/mcb.16.9.4869}}</ref>
* [[Myd88]],<ref name = pmid11416133>{{cite journal | vauthors = Jefferies C, Bowie A, Brady G, Cooke EL, Li X, O'Neill LA | title = Transactivation by the p65 subunit of NF-kappaB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1 | journal = Molecular and Cellular Biology | volume = 21 | issue = 14 | pages = 4544–52 | date = Jul 2001 | pmid = 11416133 | pmc = 87113 | doi = 10.1128/MCB.21.14.4544-4552.2001 }}</ref>
* [[Myd88]],<ref name = pmid11416133>{{cite journal | vauthors = Jefferies C, Bowie A, Brady G, Cooke EL, Li X, O'Neill LA | title = Transactivation by the p65 subunit of NF-kappaB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1 | journal = Molecular and Cellular Biology | volume = 21 | issue = 14 | pages = 4544–52 | date = Jul 2001 | pmid = 11416133 | pmc = 87113 | doi = 10.1128/MCB.21.14.4544-4552.2001 | url = http://www.tara.tcd.ie/bitstream/2262/33698/1/Transactivation%20by%20the%20p65%20subunit%20of%20NF-kappaB%20in%20response%20to%20interleukin-1%20%28IL-1%29%20involves%20MyD88%2c%20IL-1%20receptor-associated%20kinase%201%2c%20TRAF-6%2c%20and%20Rac1.pdf }}</ref>
* [[Myotonic dystrophy protein kinase|DMPK]],<ref name = pmid10869570>{{cite journal | vauthors = Shimizu M, Wang W, Walch ET, Dunne PW, Epstein HF | title = Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase | journal = FEBS Letters | volume = 475 | issue = 3 | pages = 273–7 | date = Jun 2000 | pmid = 10869570 | doi = 10.1016/S0014-5793(00)01692-6 }}</ref>
* [[Myotonic dystrophy protein kinase|DMPK]],<ref name = pmid10869570>{{cite journal | vauthors = Shimizu M, Wang W, Walch ET, Dunne PW, Epstein HF | title = Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase | journal = FEBS Letters | volume = 475 | issue = 3 | pages = 273–7 | date = Jun 2000 | pmid = 10869570 | doi = 10.1016/S0014-5793(00)01692-6 }}</ref>
* [[NCKAP1]],<ref name = pmid9148763>{{cite journal | vauthors = Kitamura Y, Kitamura T, Sakaue H, Maeda T, Ueno H, Nishio S, Ohno S, Osada S, Sakaue M, Ogawa W, Kasuga M | title = Interaction of Nck-associated protein 1 with activated GTP-binding protein Rac | journal = The Biochemical Journal | volume = 322 | issue = 3 | pages = 873–8 | date = Mar 1997 | pmid = 9148763 | pmc = 1218269 | doi =  10.1042/bj3220873}}</ref>
* [[NCKAP1]],<ref name = pmid9148763>{{cite journal | vauthors = Kitamura Y, Kitamura T, Sakaue H, Maeda T, Ueno H, Nishio S, Ohno S, Osada S, Sakaue M, Ogawa W, Kasuga M | title = Interaction of Nck-associated protein 1 with activated GTP-binding protein Rac | journal = The Biochemical Journal | volume = 322 | issue = 3 | pages = 873–8 | date = Mar 1997 | pmid = 9148763 | pmc = 1218269 | doi =  10.1042/bj3220873}}</ref>
Line 63: Line 63:
== External links ==
== External links ==
* {{MeshName|rac1+GTP-Binding+Protein}}
* {{MeshName|rac1+GTP-Binding+Protein}}
*[http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=5879 RAC1] Info with links in the [http://www.cellmigration.org/index.shtml Cell Migration Gateway]
*[https://web.archive.org/web/20110722013437/http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=5879 RAC1] Info with links in the [http://www.cellmigration.org/index.shtml Cell Migration Gateway]


{{PDB Gallery|geneid=5879}}
{{PDB Gallery|geneid=5879}}
{{GTPases}}
{{GTPases}}
{{Rho family of GTPases}}
{{Rho family of GTPases}}

Latest revision as of 14:41, 4 November 2018

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Identifiers
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Orthologs
SpeciesHumanMouse
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RefSeq (mRNA)

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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.[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

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, antimicrobial cytotoxicity,[6] and the activation of protein kinases.[7]

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

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.[8] 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.[9] Overexpression of a constitutively active Rac1 V12 in mice caused a tumor that's phenotypically indistinguishable from human Kaposi's sarcoma.[10] 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.[11] Such abnormal cell motility may result in epithelial mesenchymal transition (EMT) – a driving mechanism for tumor metastasis as well as drug-resistant tumor relapse.[12][13]

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.[5][14][15] 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[4][16] and muscle stretching[17]

Clinical significance

Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving melanoma [18][19][20] and non-small cell lung cancer.[21] As a result, Rac1 is considered a therapeutic target for many of these diseases.[22]

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.[23][24][25] 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.[24] However, given Rac1's role in glucose transport, drugs that inhibits 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.[26] Most mutations cause microcephaly while some specific changes appear to result in macrocephaly.

Interactions

RAC1 has been shown to interact with:

References

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  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. 4.0 4.1 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.
  5. 5.0 5.1 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. 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.
  7. 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.
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  10. Ma, Qi; Cavallin, Lucas E.; Yan, Bin; Zhu, Shoukang; Duran, Elda Margarita; Wang, Huili; Hale, Laura P.; Dong, Chunming; Cesarman, Ethel (2009-05-26). "Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma". Proceedings of the National Academy of Sciences. 106 (21): 8683–8688. doi:10.1073/pnas.0812688106. ISSN 0027-8424. PMC 2679580. PMID 19429708.
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  26. 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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Further reading

External links