RAC2 (ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2))

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RAC2 (ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2))

Identity

Other names EN-7

GX

Gx

HSPC022

p21-Rac2

HGNC RAC2

Location 22q13.1

Location_base_pair Starts at 35951256 and ends at 35970251 bp from pter ( according to hg18-Mar_2006).

DNA/RNA

Description The Rac2 gene sequence contains 7 exons (Courjal et al., 1997) and is expressed specifically in hematopoietic cells. Human Rac2 gene locus is silenced in non-hematopoietic cells by a mechanism that involves DNA methylation (Ladd et al., 2004). Cells that lack Rac2 expression exhibit increased cytosine methylation in the sequences flanking the gene, whereas cells that express Rac2 exhibit increased cytosine methylation within the body of the Rac2 gene.

Transcription The human Rac2 gene promoter lacks TATA and CCAAT boxes, utilizes multiple transcription initiation sites, and contains several putative Sp1 binding sites, which is common in promoters that lack TATA boxes (Ladd et al., 2004).
The transcript length is of 1471 nt translated to a 192 residues protein.

Protein

Description Rac2 protein belongs to the GTP-binding proteins of the Rho family and cycles between an active GTP-bound form and an inactive GDP-bound form. This regulatory cycle is exerted by three distinct families of proteins: guanine exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). Several GEFs have been shown to activate Rac2 selectively, Vav1 (Ming et al., 2007), Tiam1 (Haeusler et al., 2003), P-Rex1 (Welch et al., 2002), Swap70 (Sivalenka and Jessberger, 2004) and Dock2 (Nishihara et al., 2002). Two GAPs that act on Rac2 are Abr and Bcr (Chuang et al., 1995), as well as others found in leukocytes.
Rac2 function depends on association of the GTPase with membranes and subcellular localization, properties influenced by C-terminal lipid modifications, specifically is modified by the C20 GG isoprenoid.
Upon GTP loading, a conformational change takes place that allows Rac2 protein to interact with several downstream effectors that ultimately process the information and propagate the signal within the cell, causing changes in the actin cytoskeleton, release of inflammatory modulators and innate immunity. The signaling of active Rac2 is mediated by its interaction with effector proteins such as p67phox and cytochrome b-558 (Diebold and Bokoch, 2001), PLCbeta2 (Piechulek et al., 2005), nitric oxide synthase 2 (NOS2) (Kuncewicz et al., 2001) and Pak1 (Carstanjen et al., 2005).

Expression Expression is restricted to hematopoietic cells and exhibits the highest expression in myeloid cells. Rac2 expression is regulated during the differentiation of hematopoietic and myeloid cells. There is some data suggesting that Rac2 might be expressed in tumors.

Localisation Once activated Rac2 is mainly localized in endomembranes.

Function As suggested by its restricted expression, Rac2 has a specialized role in many hematopoietic and immunological processes. Rac2 deficient mice show defects in stem cells, mast cells as well as B and T cells.
Role in hematopoietic stem-cell progenitor engraftment
The contribution of the GTPase Rac2 to the normal functioning of hematopoietic stem-cell progenitors (HSC/Ps) was addressed based on the phenotype of Rac2-/- mice (Gu et al., 2003). HSC/Ps from these mice showed normal short-term engraftment, but decreased adhesion, suggesting a key role for Rac2 in integrin-mediated stem-cell adhesion. In addition, Rac2-/- HSC/Ps formed colonies with both impaired growth and migration, and showed an increased rate of apoptosis.
In response to stromal derived factor 1, Rac2-/- cells failed in cortical F-actin assembly, and presented reduced cell spreading and actin-based membrane protrusion.
Role in neutrophils function
Several reports point out Rac2 is the predominant Rac GTPase functioning in neutrophils. These observations came from studies in neutrophils from Rac2-/- mice and a patient with a dominant-negative Rac2 mutation in which these cells showed decreased motility, adhesion, major defects in cortical F-actin assembly, and accordingly, chemotaxis and reduced phagocytosis and superoxide production by NAPH oxidase (Williams et al., 2000; Roberts et al., 1999; Li et al., 2002; Gu et al., 2003). Rac2 is required for oxidase activity through its direct interaction with p67-phox and cytochrome b 558.
Role in B-cell development
Rac2-/- mice exhibit multiple defects in B-cell development, with reduced numbers of peripheral blood B-cells and IgM-secreting plasma cells, a severe reduction in the number of marginal zone and peritoneal B1 cells (Croker et al., 2002). Rac2 participates in the positive selection through the B-cell receptor (BCR), since is activated by BCR cross-linking (Grill and Schrader, 2002).
Role in T-cell differentiation
Rac2 activity is required for interferon-gamma (IFNgamma) production both in vitro and in vivo during normal T-cell activation and Th1-cell differentiation, through simultaneous activation of both the NFkappaB and p38 pathways (Li et al., 2000).
Role in Mast cell survival
The absence of Rac2 results in defects growth, survival, chemotaxis, adhesion, and degranulation in mast cell (Yang et al., 2000). Rac2 is critical in regulating the growth factor-induced survival through activation of Akt and a change in expression levels of the Bcl-2 family members BAD and Bcl-XL (Yang et al., 2000).

Homology Rac2 share significant sequence identity (~88%) with the other two members of the subfamily Rac: Rac1 and Rac3. The three proteins diverge primarily in the C-terminal 15 residues. Regarding to the biochemical properties, Rac2 shows a slower nucleotide association and is more efficiently activated by the Rac-GEF Tiam1 than Rac1 and Rac3.

Mutations

Note POLYMORPHISMS
Two single nucleotide polymorphisms (SNP) have been observed in gliomas (Idbaih et al., 2008). The SNPs rs2239774 in exon 2 (codon 27, GCC to GCG, Ala to Ala) and rs3179967 in exon 6 (codon 159, GCT to GCC, Ala to Ala) were observed in 15/78 and 7/78 cases, respectively. No association between these two SNPs with phenotype, tumor grade, patient age, and patient gender was seen.

Germinal A point mutation has been identified in one allele of the Rac2 gene resulting in the substitution of Asp57 by an Asn (Rac2^D57N) in a patient with a primary immunodeficiency syndrome (Ambruso et al., 2000; Williams et al., 2000). Rac2^D57N binds GDP but not GTP and inhibits oxidase activation and superoxide production in vitro.

Somatic So far only two studies have searched for the presence of somatic mutations, both of them analyzed human brain tumors. Hwang et al. found 26% of cases had Rac2 gene mutation, two cases with decreased Rac2 expression and four cases with normal Rac2 expression. One case showed the mutation site nearby the GTP-binding site, which may affect Rac2 GTPase activity, but the site of Rac2 mutation seems not to concentrate in the effector region. However, Idbaih et al. did not find missense mutations in a series of 78 gliomas.

Implicated in

Entity Immunodeficiency

Disease Lack of Rac2 activity causes immunodeficiency (Ambruso et al., 2000; Williams et al., 2000). A single patient was identified with a primary immunodeficiency syndrome resulting from a heterozygous mutation in the Rac2 gene. In the first 5 months after birth, the patient presented several bacterial infections, poor wound healing, and absence of pus in the wounds, indicative of a phagocyte defect. The neutrophils had decreased chemotactic motility, polarization, and secretion of azurophilic granules. Rac2 levels were reduced, suggesting a defect in this GTPase. Western blot analysis of lysates from patient neutrophils demonstrated decreased levels of Rac2 protein. Molecular analysis identified a point mutation in one allele of the Rac2 gene resulting in the substitution of Asp57 by an Asn (Rac2^D57N). Rac2^D57N inhibits oxidase activation and superoxide production in vitro. These data represent the description of an inhibitory mutation in a member of the Rho family of GTPases associated with a human immunodeficiency syndrome.

Entity Brain tumors

Oncogenesis Expression of Rac2 was examined by RT-PCR and Northern blotting in human brain tumors: 10 astrocytomas, 8 meningiomas, and 8 pituitary adenomas (Hwang et al., 2005). The overexpression of Rac2 was evident in 1/10 astrocytomas and 1/8 meningiomas. No overexpression was found in pituitary adenomas. The decreased expression of Rac2 was found in 15 of 26 brain tumors (8/10 astrocytomas, 2/8 meningiomas and 5/8 pituitary adenomas).

Entity Head and neck squamous cell cancer

Oncogenesis Western blot analysis showed increased expression of Rac2 in a malignant squamous cell cancer cell line and a premalignant dysplastic cell line compared to the normal human epidermal keratinocytes (Abraham et al., 2001). This observation was confirmed with an immunohistochemical study of 15 moderately to poorly differentiated head and neck squamous cell cancer specimens, where a specific increased expression of Rac2 in areas of squamous cell cancer compared to the normal tissue was observed. Rac2 shows nuclear staining in normal human epidermal keratinocytes increasing sequentially in premalignant and malignant cell lines. In addition, there is specific cytoplasmic staining of the malignant cancer cell line which is absent in the normal and premalignant cell lines. This differential cytoplasmic staining may be able to distinguish invasive squamous cell carcinoma from dysplastic lesions and benign normal mucosa. Consequently it has been proposed that this GTPase could have an important role in the diagnosis and staging of this tumor type.

Entity Acute myeloid leukemia (AML)

Oncogenesis Activating mutations of KIT, which encodes the receptor for the cytokine stem cell factor, have been described in acute myeloid leukemia. Genetic disruption of Rac2 or pharmacologic evidence through treatment with Rac inhibitor NC23766, implicate Rac2 in regulating KIT-induced transformation in acute myeloid leukaemia (Munugalavadla et al., 2007). These results suggest Rac2 as a potential novel therapeutic target for the treatment of KIT-bearing acute myeloid leukemia.

Entity Chronic myelogenous leukemia (CML)

Oncogenesis Gene targeting of Rac1 and Rac2 significantly delays or abrogates development of chronic myelogenous leukemia (CML), a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR- ABL fusion protein (Thomas et al., 2007). These genetic data were further substantiated experimentally by use of NSC23766, small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo. These findings indicate that Rac GTPases are critical for p210-BCR-ABL-mediated transformation and, therefore, suggest that the Rac GTPases may prove to be useful therapeutically by targeting alternative signaling pathways, which may be responsible for resistance and relapse in CML.

External links

Nomenclature
HGNC RAC2   9802

Entrez_Gene RAC2  5880  ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)

Cards
Atlas RAC2ID42021ch22q13

GeneCards RAC2

Ensembl RAC2 [Search_View]   ENSG00000128340 [Gene_View]  RAC2 [Vega]

Genatlas RAC2
GeneLynx RAC2

eGenome RAC2

euGene 5880

Genomic and cartography
GoldenPath RAC2 - 22q13.1   chr22:35951256-35970251 - 22q13.1   [Description]    (hg18-Mar_2006)

Ensembl RAC2 - 22q13.1 [CytoView]
NCBI Mapview

OMIM Disease map [OMIM]

HomoloGene RAC2

Gene and transcription
Genbank AF077208 [ ENTREZ ]

Genbank AF498965 [ ENTREZ ]

Genbank AK096924 [ ENTREZ ]

Genbank BC001485 [ ENTREZ ]

Genbank BC018735 [ ENTREZ ]

RefSeq NM_002872 [ SRS ]    NM_002872 [ ENTREZ ]

RefSeq AC_000065 [ SRS ]    AC_000065 [ ENTREZ ]

RefSeq AC_000154 [ SRS ]    AC_000154 [ ENTREZ ]

RefSeq NC_000022 [ SRS ]    NC_000022 [ ENTREZ ]

RefSeq NG_007288 [ SRS ]    NG_007288 [ ENTREZ ]

RefSeq NT_011520 [ SRS ]    NT_011520 [ ENTREZ ]

RefSeq NW_001838745 [ SRS ]    NW_001838745 [ ENTREZ ]

RefSeq NW_927628 [ SRS ]    NW_927628 [ ENTREZ ]

CCDS RAC2 CCDS - NCBI

AceView RAC2 AceView - NCBI

Unigene Hs.517601 [ SRS ]    Hs.517601 [ NCBI ]     HS517601 [ spliceNest ]

Fast-db 5666 (alternative variants)

Protein : pattern, domain, 3D structure
SwissProt P15153 [ SRS]    P15153 [ EXPASY ]     P15153 [ INTERPRO ]     P15153 [ UNIPROT ] P15153 [ VarSplice ]

Interpro IPR003578 GTPase_Rho [ SRS ]    IPR003578 GTPase_Rho [ EBI ]

Interpro IPR013753 Ras [ SRS ]    IPR013753 Ras [ EBI ]

Interpro IPR001806 Ras_trnsfrmng [ SRS ]    IPR001806 Ras_trnsfrmng [ EBI ]

Interpro IPR005225 Small_GTP_bd [ SRS ]    IPR005225 Small_GTP_bd [ EBI ]

CluSTr P15153

Pfam PF00071 Ras [ SRS ]    PF00071 Ras [ Sanger ]    pfam00071 [ NCBI-CDD ]

Smart SM00174 RHO [EMBL]

Blocks P15153

PDB 1DS6 [ SRS ]    1DS6 [ PdbSum ],   1DS6 [ IMB ]   1DS6 [ RSDB ]

HPRD 03628

Protein Interaction databases
DIP P15153
IntAct P15153
Polymorphism : SNP, mutations, diseases
OMIM 602049;608203    [ map ]

GENECLINICS 602049;608203

SNP RAC2 [dbSNP-NCBI]

SNP NM_002872 [SNP-NCI]
SNP RAC2 [GeneSNPs - Utah]  RAC2] [HGBASE - SRS]

HAPMAP RAC2 [HAPMAP]

COSMIC RAC2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD RAC2

Genetic Association RAC2

CDC HuGE RAC2

General knowledge
Family Browser RAC2 [UCSC Family Browser]

SOURCE NM_002872

SMD Hs.517601

SAGE Hs.517601

GO nucleotide binding [Amigo]  nucleotide binding

GO GTPase activity [Amigo]  GTPase activity

GO protein binding [Amigo]  protein binding

GO GTP binding [Amigo]  GTP binding

GO intracellular [Amigo]  intracellular

GO membrane fraction [Amigo]  membrane fraction

GO nuclear envelope [Amigo]  nuclear envelope

GO cytoplasm [Amigo]  cytoplasm

GO chemotaxis [Amigo]  chemotaxis

GO signal transduction [Amigo]  signal transduction

GO small GTPase mediated signal transduction [Amigo]  small GTPase mediated signal transduction

GO positive regulation of cell proliferation [Amigo]  positive regulation of cell proliferation

GO regulation of hydrogen peroxide metabolic process [Amigo]  regulation of hydrogen peroxide metabolic process

GO cell projection biogenesis [Amigo]  cell projection biogenesis

GO actin cytoskeleton organization and biogenesis [Amigo]  actin cytoskeleton organization and biogenesis

GO regulation of respiratory burst [Amigo]  regulation of respiratory burst

KEGG MAPK signaling pathway

KEGG Wnt signaling pathway

KEGG Axon guidance

KEGG VEGF signaling pathway

KEGG Focal adhesion

KEGG Adherens junction

KEGG Natural killer cell mediated cytotoxicity

KEGG B cell receptor signaling pathway

KEGG Fc epsilon RI signaling pathway

KEGG Leukocyte transendothelial migration

KEGG Regulation of actin cytoskeleton

KEGG Colorectal cancer

PubGene RAC2

TreeFam RAC2

CTD 5880 [Comparative ToxicoGenomics Database]

Other databases
Probes
Probe RAC2 Related clones (RZPD - Berlin)

PubMed
PubMed 49 Pubmed reference(s) in Entrez

	Nomenclature
HGNC	RAC2 9802
Entrez_Gene	RAC2 5880 ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)
	Cards
Atlas	RAC2ID42021ch22q13
GeneCards	RAC2
Ensembl	RAC2 [Search_View] ENSG00000128340 [Gene_View] RAC2 [Vega]
Genatlas	RAC2
GeneLynx	RAC2
eGenome	RAC2
euGene	5880
	Genomic and cartography
GoldenPath	RAC2 - 22q13.1 chr22:35951256-35970251 - 22q13.1 [Description] (hg18-Mar_2006)
Ensembl	RAC2 - 22q13.1 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	RAC2
	Gene and transcription
Genbank	AF077208 [ ENTREZ ]
Genbank	AF498965 [ ENTREZ ]
Genbank	AK096924 [ ENTREZ ]
Genbank	BC001485 [ ENTREZ ]
Genbank	BC018735 [ ENTREZ ]
RefSeq	NM_002872 [ SRS ] NM_002872 [ ENTREZ ]
RefSeq	AC_000065 [ SRS ] AC_000065 [ ENTREZ ]
RefSeq	AC_000154 [ SRS ] AC_000154 [ ENTREZ ]
RefSeq	NC_000022 [ SRS ] NC_000022 [ ENTREZ ]
RefSeq	NG_007288 [ SRS ] NG_007288 [ ENTREZ ]
RefSeq	NT_011520 [ SRS ] NT_011520 [ ENTREZ ]
RefSeq	NW_001838745 [ SRS ] NW_001838745 [ ENTREZ ]
RefSeq	NW_927628 [ SRS ] NW_927628 [ ENTREZ ]
CCDS	RAC2 CCDS - NCBI
AceView	RAC2 AceView - NCBI
Unigene	Hs.517601 [ SRS ] Hs.517601 [ NCBI ] HS517601 [ spliceNest ]
Fast-db	5666 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P15153 [ SRS] P15153 [ EXPASY ] P15153 [ INTERPRO ] P15153 [ UNIPROT ] P15153 [ VarSplice ]
Interpro	IPR003578 GTPase_Rho [ SRS ] IPR003578 GTPase_Rho [ EBI ]
Interpro	IPR013753 Ras [ SRS ] IPR013753 Ras [ EBI ]
Interpro	IPR001806 Ras_trnsfrmng [ SRS ] IPR001806 Ras_trnsfrmng [ EBI ]
Interpro	IPR005225 Small_GTP_bd [ SRS ] IPR005225 Small_GTP_bd [ EBI ]
CluSTr	P15153
Pfam	PF00071 Ras [ SRS ] PF00071 Ras [ Sanger ] pfam00071 [ NCBI-CDD ]
Smart	SM00174 RHO [EMBL]
Blocks	P15153
PDB	1DS6 [ SRS ] 1DS6 [ PdbSum ], 1DS6 [ IMB ] 1DS6 [ RSDB ]
HPRD	03628
	Protein Interaction databases
DIP	P15153
IntAct	P15153
	Polymorphism : SNP, mutations, diseases
OMIM	602049;608203 [ map ]
GENECLINICS	602049;608203
SNP	RAC2 [dbSNP-NCBI]
SNP	NM_002872 [SNP-NCI]
SNP	RAC2 [GeneSNPs - Utah] RAC2] [HGBASE - SRS]
HAPMAP	RAC2 [HAPMAP]
COSMIC	RAC2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	RAC2
Genetic Association	RAC2
CDC HuGE	RAC2
	General knowledge
Family Browser	RAC2 [UCSC Family Browser]
SOURCE	NM_002872
SMD	Hs.517601
SAGE	Hs.517601
GO	nucleotide binding [Amigo] nucleotide binding
GO	GTPase activity [Amigo] GTPase activity
GO	protein binding [Amigo] protein binding
GO	GTP binding [Amigo] GTP binding
GO	intracellular [Amigo] intracellular
GO	membrane fraction [Amigo] membrane fraction
GO	nuclear envelope [Amigo] nuclear envelope
GO	cytoplasm [Amigo] cytoplasm
GO	chemotaxis [Amigo] chemotaxis
GO	signal transduction [Amigo] signal transduction
GO	small GTPase mediated signal transduction [Amigo] small GTPase mediated signal transduction
GO	positive regulation of cell proliferation [Amigo] positive regulation of cell proliferation
GO	regulation of hydrogen peroxide metabolic process [Amigo] regulation of hydrogen peroxide metabolic process
GO	cell projection biogenesis [Amigo] cell projection biogenesis
GO	actin cytoskeleton organization and biogenesis [Amigo] actin cytoskeleton organization and biogenesis
GO	regulation of respiratory burst [Amigo] regulation of respiratory burst
KEGG	MAPK signaling pathway
KEGG	Wnt signaling pathway
KEGG	Axon guidance
KEGG	VEGF signaling pathway
KEGG	Focal adhesion
KEGG	Adherens junction
KEGG	Natural killer cell mediated cytotoxicity
KEGG	B cell receptor signaling pathway
KEGG	Fc epsilon RI signaling pathway
KEGG	Leukocyte transendothelial migration
KEGG	Regulation of actin cytoskeleton
KEGG	Colorectal cancer
PubGene	RAC2
TreeFam	RAC2
CTD	5880 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	RAC2 Related clones (RZPD - Berlin)
	PubMed
PubMed	49 Pubmed reference(s) in Entrez

Bibliography

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Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense.

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Immunity 1999; 10: 183-196.

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Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation.

Ambruso DR, Knall C, Abell AN, Panepinto J, Kurkchubasche A, Thurman G, Gonzalez-Aller C, Hiester A, deBoer M, Harbeck RJ, Oyer R, Johnson GL, Roos D.

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Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation.

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Science 2000; 288: 2219-2222.

PMID 10864872

Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency.

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PMID 10961859

Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells.

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Immunity 2000; 12: 557-568.

PMID 10843388

Motility-related proteins as markers for head and neck squamous cell cancer.

Abraham MT, Kuriakose MA, Sacks PG, Yee H, Chiriboga L, Bearer EL, Delacure MD.

Laryngoscope 2001;111: 1285-1289.

PMID 11568556

Molecular basis for Rac2 regulation of phagocyte NADPH oxidase.

Diebold BA, Bokoch GM.

Nat Immunol 2001; 2: 211-215.

PMID 11224519

Specific association of nitric oxide synthase-2 with Rac isoforms in activated murine macrophages.

Kuncewicz T, Balakrishnan P, Snuggs MB, Kone BC.

Am J Physiol Renal Physiol 2001; 281: F326-F336.

PMID 11457725

The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes.

Croker BA, Tarlinton DM, Cluse LA, Tuxen AJ, Light A, Yang FC, Williams DA, Roberts AW.

J Immunol 2002; 168: 3376-3386.

PMID 11907095

Activation of Rac-1, Rac-2, and Cdc42 by hemopoietic growth factors or cross-linking of the B-lymphocyte receptor for antigen.

Grill B, Schrader JW.

Blood 2002; 100: 3183-3192.

PMID 12384416

DOCK2 mediates T cell receptor-induced activation of Rac2 and IL-2 transcription.

Nishihara H, Maeda M, Tsuda M, Makino Y, Sawa H, Nagashima K, Tanaka S.

Biochem Biophys Res Commun 2002; 296: 716-720.

PMID 12176041

P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac.

Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR.

Cell 2002; 108: 809-821.

PMID 11955434

Comparative functional analysis of the Rac GTPases.

Haeusler LC, Blumenstein L, Stege P, Dvorsky R, Ahmadian MR.

FEBS Lett 2003; 555: 556-560.

PMID 14675773

Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases.

Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC, Harris CE, Lee AW, Prabhakar R, Atkinson SJ, Kwiatkowski DJ, Williams DA.

Science 2003; 302: 445-449.

PMID 14564009

Identification of a genomic fragment that directs hematopoietic-specific expression of Rac2 and analysis of the DNA methylation profile of the gene locus.

Ladd PD, Butler JS, Skalnik DG.

Gene 2004; 341: 323-333.

PMID 15474314

SWAP-70 regulates c-kit-induced mast cell activation, cell-cell adhesion, and migration.

Sivalenka RR, Jessberger R.

Mol Cell Biol 2004; 24: 10277-10288.

PMID 15542837

Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways.

Carstanjen D, Yamauchi A, Koornneef A, Zang H, Filippi MD, Harris C, Towe J, Atkinson S, Zheng Y, Dinauer MC, Williams DA.

J Immunol 2005; 174: 4613-4620.

PMID 15814684

Rho GTPase expression in tumourigenesis: evidence for a significant link.

Gómez del Pulgar T, Benitah SA, Valerón PF, Espina C, Lacal JC.

Bioessays 2005; 27: 602-613. (REVIEW)

PMID 15892119

Rac2 expression and mutation in human brain tumors.

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Acta Neurochir (Wien) 2005; 147: 551-554.

PMID 15812594

Isozyme-specific stimulation of phospholipase C-gamma2 by Rac GTPases.

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PMID 16172125

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Mol Cell Biol 2007; 27: 312-323.

PMID 17060455

Genetic and pharmacologic evidence implicating the p85 alpha, but not p85 beta, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis.

Munugalavadla V, Sims EC, Borneo J, Chan RJ, Kapur R.

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PMID 17483298

Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease.

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PMID 17996650

Mutational analysis of Rac2 in gliomas.

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PMID 18217210

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Search in all EBI NCBI

Contributor(s)

Written 08-2008 Teresa Gómez del Pulgar, Juan Carlos Lacal

Centro Nacional de Biotecnología (CNB), Darwin 3, 28049 Madrid, Spain

Citation

This paper should be referenced as such :
Gómez del Pulgar T, Lacal JC . RAC2 (ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)). Atlas Genet Cytogenet Oncol Haematol. August 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/RAC2ID42021ch22q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sun Nov 9 19:46:23 2008

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us
jlhuret@AtlasGeneticsOncology.org.

Other names	EN-7
	GX
	Gx
	HSPC022
	p21-Rac2
HGNC	RAC2
Location	22q13.1
Location_base_pair	Starts at 35951256 and ends at 35970251 bp from pter ( according to hg18-Mar_2006).

Description	Rac2 protein belongs to the GTP-binding proteins of the Rho family and cycles between an active GTP-bound form and an inactive GDP-bound form. This regulatory cycle is exerted by three distinct families of proteins: guanine exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). Several GEFs have been shown to activate Rac2 selectively, Vav1 (Ming et al., 2007), Tiam1 (Haeusler et al., 2003), P-Rex1 (Welch et al., 2002), Swap70 (Sivalenka and Jessberger, 2004) and Dock2 (Nishihara et al., 2002). Two GAPs that act on Rac2 are Abr and Bcr (Chuang et al., 1995), as well as others found in leukocytes. Rac2 function depends on association of the GTPase with membranes and subcellular localization, properties influenced by C-terminal lipid modifications, specifically is modified by the C20 GG isoprenoid. Upon GTP loading, a conformational change takes place that allows Rac2 protein to interact with several downstream effectors that ultimately process the information and propagate the signal within the cell, causing changes in the actin cytoskeleton, release of inflammatory modulators and innate immunity. The signaling of active Rac2 is mediated by its interaction with effector proteins such as p67phox and cytochrome b-558 (Diebold and Bokoch, 2001), PLCbeta2 (Piechulek et al., 2005), nitric oxide synthase 2 (NOS2) (Kuncewicz et al., 2001) and Pak1 (Carstanjen et al., 2005).
Expression	Expression is restricted to hematopoietic cells and exhibits the highest expression in myeloid cells. Rac2 expression is regulated during the differentiation of hematopoietic and myeloid cells. There is some data suggesting that Rac2 might be expressed in tumors.
Localisation	Once activated Rac2 is mainly localized in endomembranes.
Function	As suggested by its restricted expression, Rac2 has a specialized role in many hematopoietic and immunological processes. Rac2 deficient mice show defects in stem cells, mast cells as well as B and T cells. Role in hematopoietic stem-cell progenitor engraftment The contribution of the GTPase Rac2 to the normal functioning of hematopoietic stem-cell progenitors (HSC/Ps) was addressed based on the phenotype of Rac2-/- mice (Gu et al., 2003). HSC/Ps from these mice showed normal short-term engraftment, but decreased adhesion, suggesting a key role for Rac2 in integrin-mediated stem-cell adhesion. In addition, Rac2-/- HSC/Ps formed colonies with both impaired growth and migration, and showed an increased rate of apoptosis. In response to stromal derived factor 1, Rac2-/- cells failed in cortical F-actin assembly, and presented reduced cell spreading and actin-based membrane protrusion. Role in neutrophils function Several reports point out Rac2 is the predominant Rac GTPase functioning in neutrophils. These observations came from studies in neutrophils from Rac2-/- mice and a patient with a dominant-negative Rac2 mutation in which these cells showed decreased motility, adhesion, major defects in cortical F-actin assembly, and accordingly, chemotaxis and reduced phagocytosis and superoxide production by NAPH oxidase (Williams et al., 2000; Roberts et al., 1999; Li et al., 2002; Gu et al., 2003). Rac2 is required for oxidase activity through its direct interaction with p67-phox and cytochrome b 558. Role in B-cell development Rac2-/- mice exhibit multiple defects in B-cell development, with reduced numbers of peripheral blood B-cells and IgM-secreting plasma cells, a severe reduction in the number of marginal zone and peritoneal B1 cells (Croker et al., 2002). Rac2 participates in the positive selection through the B-cell receptor (BCR), since is activated by BCR cross-linking (Grill and Schrader, 2002). Role in T-cell differentiation Rac2 activity is required for interferon-gamma (IFNgamma) production both in vitro and in vivo during normal T-cell activation and Th1-cell differentiation, through simultaneous activation of both the NFkappaB and p38 pathways (Li et al., 2000). Role in Mast cell survival The absence of Rac2 results in defects growth, survival, chemotaxis, adhesion, and degranulation in mast cell (Yang et al., 2000). Rac2 is critical in regulating the growth factor-induced survival through activation of Akt and a change in expression levels of the Bcl-2 family members BAD and Bcl-XL (Yang et al., 2000).
Homology	Rac2 share significant sequence identity (~88%) with the other two members of the subfamily Rac: Rac1 and Rac3. The three proteins diverge primarily in the C-terminal 15 residues. Regarding to the biochemical properties, Rac2 shows a slower nucleotide association and is more efficiently activated by the Rac-GEF Tiam1 than Rac1 and Rac3.

Note	POLYMORPHISMS Two single nucleotide polymorphisms (SNP) have been observed in gliomas (Idbaih et al., 2008). The SNPs rs2239774 in exon 2 (codon 27, GCC to GCG, Ala to Ala) and rs3179967 in exon 6 (codon 159, GCT to GCC, Ala to Ala) were observed in 15/78 and 7/78 cases, respectively. No association between these two SNPs with phenotype, tumor grade, patient age, and patient gender was seen.
Germinal	A point mutation has been identified in one allele of the Rac2 gene resulting in the substitution of Asp57 by an Asn (Rac2^D57N) in a patient with a primary immunodeficiency syndrome (Ambruso et al., 2000; Williams et al., 2000). Rac2^D57N binds GDP but not GTP and inhibits oxidase activation and superoxide production in vitro.
Somatic	So far only two studies have searched for the presence of somatic mutations, both of them analyzed human brain tumors. Hwang et al. found 26% of cases had Rac2 gene mutation, two cases with decreased Rac2 expression and four cases with normal Rac2 expression. One case showed the mutation site nearby the GTP-binding site, which may affect Rac2 GTPase activity, but the site of Rac2 mutation seems not to concentrate in the effector region. However, Idbaih et al. did not find missense mutations in a series of 78 gliomas.

Entity	Immunodeficiency
Disease	Lack of Rac2 activity causes immunodeficiency (Ambruso et al., 2000; Williams et al., 2000). A single patient was identified with a primary immunodeficiency syndrome resulting from a heterozygous mutation in the Rac2 gene. In the first 5 months after birth, the patient presented several bacterial infections, poor wound healing, and absence of pus in the wounds, indicative of a phagocyte defect. The neutrophils had decreased chemotactic motility, polarization, and secretion of azurophilic granules. Rac2 levels were reduced, suggesting a defect in this GTPase. Western blot analysis of lysates from patient neutrophils demonstrated decreased levels of Rac2 protein. Molecular analysis identified a point mutation in one allele of the Rac2 gene resulting in the substitution of Asp57 by an Asn (Rac2^D57N). Rac2^D57N inhibits oxidase activation and superoxide production in vitro. These data represent the description of an inhibitory mutation in a member of the Rho family of GTPases associated with a human immunodeficiency syndrome.

Entity	Brain tumors
Oncogenesis	Expression of Rac2 was examined by RT-PCR and Northern blotting in human brain tumors: 10 astrocytomas, 8 meningiomas, and 8 pituitary adenomas (Hwang et al., 2005). The overexpression of Rac2 was evident in 1/10 astrocytomas and 1/8 meningiomas. No overexpression was found in pituitary adenomas. The decreased expression of Rac2 was found in 15 of 26 brain tumors (8/10 astrocytomas, 2/8 meningiomas and 5/8 pituitary adenomas).

Entity	Head and neck squamous cell cancer
Oncogenesis	Western blot analysis showed increased expression of Rac2 in a malignant squamous cell cancer cell line and a premalignant dysplastic cell line compared to the normal human epidermal keratinocytes (Abraham et al., 2001). This observation was confirmed with an immunohistochemical study of 15 moderately to poorly differentiated head and neck squamous cell cancer specimens, where a specific increased expression of Rac2 in areas of squamous cell cancer compared to the normal tissue was observed. Rac2 shows nuclear staining in normal human epidermal keratinocytes increasing sequentially in premalignant and malignant cell lines. In addition, there is specific cytoplasmic staining of the malignant cancer cell line which is absent in the normal and premalignant cell lines. This differential cytoplasmic staining may be able to distinguish invasive squamous cell carcinoma from dysplastic lesions and benign normal mucosa. Consequently it has been proposed that this GTPase could have an important role in the diagnosis and staging of this tumor type.

Entity	Acute myeloid leukemia (AML)
Oncogenesis	Activating mutations of KIT, which encodes the receptor for the cytokine stem cell factor, have been described in acute myeloid leukemia. Genetic disruption of Rac2 or pharmacologic evidence through treatment with Rac inhibitor NC23766, implicate Rac2 in regulating KIT-induced transformation in acute myeloid leukaemia (Munugalavadla et al., 2007). These results suggest Rac2 as a potential novel therapeutic target for the treatment of KIT-bearing acute myeloid leukemia.

Entity	Chronic myelogenous leukemia (CML)
Oncogenesis	Gene targeting of Rac1 and Rac2 significantly delays or abrogates development of chronic myelogenous leukemia (CML), a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR- ABL fusion protein (Thomas et al., 2007). These genetic data were further substantiated experimentally by use of NSC23766, small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo. These findings indicate that Rac GTPases are critical for p210-BCR-ABL-mediated transformation and, therefore, suggest that the Rac GTPases may prove to be useful therapeutically by targeting alternative signaling pathways, which may be responsible for resistance and relapse in CML.

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Written	08-2008	Teresa Gómez del Pulgar, Juan Carlos Lacal
		Centro Nacional de Biotecnología (CNB), Darwin 3, 28049 Madrid, Spain