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'''Rho guanine nucleotide exchange factor 6''' is a [[protein]] that, in humans, is encoded by the ''ARHGEF6'' [[gene]].<ref name="pmid7584048">{{cite journal | vauthors = Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S | title = Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1 (supplement) | journal = DNA Res | volume = 1 | issue = 5 | pages = 251–62 |date=Dec 1995 | pmid = 7584048 | pmc = | doi =10.1093/dnares/1.5.251 }}</ref><ref name="pmid9659915">{{cite journal | vauthors = Manser E, Loo TH, Koh CG, Zhao ZS, Chen XQ, Tan L, Tan I, Leung T, Lim L | title = PAK kinases are directly coupled to the PIX family of nucleotide exchange factors | journal = Mol Cell | volume = 1 | issue = 2 | pages = 183–92 |date=Jul 1998 | pmid = 9659915 | pmc = | doi =10.1016/S1097-2765(00)80019-2 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ARHGEF6 Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9459| accessdate = }}</ref>
'''Rho guanine nucleotide exchange factor 6''' is a [[protein]] that, in humans, is encoded by the ''ARHGEF6'' [[gene]].<ref name="pmid7584048">{{cite journal | vauthors = Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S | title = Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1 (supplement) | journal = DNA Res | volume = 1 | issue = 5 | pages = 251–62 |date=Dec 1995 | pmid = 7584048 | pmc = | doi =10.1093/dnares/1.5.251 }}</ref><ref name="pmid9659915">{{cite journal | vauthors = Manser E, Loo TH, Koh CG, Zhao ZS, Chen XQ, Tan L, Tan I, Leung T, Lim L | title = PAK kinases are directly coupled to the PIX family of nucleotide exchange factors | journal = Mol Cell | volume = 1 | issue = 2 | pages = 183–92 |date=Jul 1998 | pmid = 9659915 | pmc = | doi =10.1016/S1097-2765(00)80019-2 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ARHGEF6 Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9459| accessdate = }}</ref>


ARHGEF6 is commonly known as the <u>p</u>21-<u>a</u>ctivated protein kinase e<u>x</u>change factor alpha (alpha-PIX or αPIX), because it was identified by binding to [[p21-activated kinases |p21-activated kinase (PAK)]] and also contains a [[guanine nucleotide exchange factor]] [[protein domain |domain]].<ref name="pmid9659915"/>
Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. The encoded protein belongs to a family of cytoplasmic proteins that catalyse the exchange of GDP for GTP in some Rho-family small GTPases. It may form a complex with G proteins and stimulate Rho-dependent signals. This protein is activated by PI3-kinase. Mutations in this gene can cause X-chromosomal non-specific mental retardation.<ref name="entrez"/>

== Domains and functions ==
αPIX is a multidomain protein that functions both as a [[cell signaling |signaling]] [[scaffold protein]] and as an [[enzyme]].<ref name=”pmid27182061”>{{cite journal | vauthors = Zhou W, Li X, Premont RT | title = Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT-PIX complexes | journal = Journal of Cell Science | volume = 129 | issue = 10 | pages = 1963-1974 | date = May 2016 | pmid = 27182061 | pmc = 6518221 | doi = 10.1242/jcs.179465 | access-date = }}</ref> αPIX shares this domain structure and signaling function with the highly similar [[ARHGEF7 |ARHGEF7/βPIX]] protein.
αPIX contains a central [[RhoGEF domain |DH/PH RhoGEF domain]] that functions as a [[guanine nucleotide exchange factor |guanine nucleotide exchange factor (GEF)]] for [[small GTPases]] of the [[Rho family]], and specifically [[Rac (GTPase) |Rac]] and [[Cdc42]].<ref name="pmid9659915"/> Like other GEFs, αPIX can promote both release of [[guanosine diphosphate |GDP]] from an inactive small GTP-binding protein and binding of [[guanosine triphosphate |GTP]] to promote its activation.
Signaling scaffolds bind to specific partners to promote efficient signal transduction by arranging sequential elements of a pathway near each other to facilitate interaction/information transfer, and also by holding these partner protein complexes in specific locations within the cell to promote local or regional signaling. In the case of αPIX, its [[SH3 domain]] binds to partner proteins with appropriate polyproline motifs, and particularly to group I [[p21-activated kinases |p21-activated kinases (PAKs)]] ([[PAK1]], [[PAK2]] and [[PAK3]]).<ref name="pmid9659915"/> PAK is bound to the αPIX SH3 domain in the inactive state, and activated Rac1 or Cdc42 binding to this PAK stimulates its [[protein kinase]] activity leading to downstream target protein [[phosphorylation]]; since αPIX can activate the “p21’’ small GTPases Rac1 or Cdc42 through its GEF activity, this αPIX/PAK/Rac complex exemplifies a scaffolding function.
Structurally, αPIX assembles as a trimer through its carboxyl-terminal coiled-coil domain, and further interacts with dimers of [[GIT1]] or [[GIT2]] through a nearby GIT-binding domain to form oligomeric GIT-PIX complexes.<ref name=”pmid27182061”/> Through this GIT-PIX complex, the scaffolding function of αPIX is amplified by also being able to hold GIT partners in proximity to αPIX partners.
⚫
αPIX contains an amino-terminal [[Calponin homology (CH) domain |Calponin Homology (CH) domain]] whose functions remain relatively poorly defined, but interacts with [[PARVB |parvin/affixin family]] proteins. <ref name = “pmid12499396”>{{cite journal | vauthors=Rosenberger G, Jantke I, Gal A, Kutsche K |title=Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling |journal=Human Molecular Genetics |volume=12 |issue= 2 |pages= 155–167 |year= 2003 |pmid= 12499396 |doi=10.1093/hmg/ddg019 }}</ref><ref name=”pmid27182061”/>

Because the ARHGEF6 gene is located on the [[X chromosome]] so that males have only one copy, mutations in this gene in humans can cause [[X-linked intellectual disability | X-chromosome-linked non-specific intellectual disability]], <ref name = “pmid11017088”>{{cite journal | vauthors= Kutsche K, Yntema H, Brandt A, Jantke I, Nothwang HG, Orth U, Boavida MG, David D, Chelly J, Fryns JP, Moraine C, Ropers HH, Hamel BC, van Bokhoven H, Gal A |title=Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation |journal=Nature Genetics |volume=26 |issue= 2 |pages= 247–250 |year= 2000 |pmid= 11017088 |doi= 10.1038/80002 }}</ref> as can mutations affecting its binding partner PAK3 whose gene is also located on the X chromosome.<ref name=”pmid9731525”>{{cite journal | vauthors = Allen KM, Gleeson JG, Bagrodia S, Partington MW, MacMillan JC, Cerione RA, Mulley JC, Walsh CA | title = PAK3 mutation in nonsyndromic X-linked mental retardation | journal = Nature Genetics | volume = 20| issue = 1 | pages = 25-30 | date = September 1998 | pmid = 9731525 | pmc = | doi = 10.1038/1675 | access-date = }}</ref>
In animal models, loss of ARHGEF6 gene function is associated with [[neuron |neuronal]] [[synapse]] defects,<ref name=”pmid21989057”>{{cite journal | vauthors = Ramakers GJ, Wolfer D, Rosenberger G, Kuchenbecker K, Kreienkamp HJ, Prange-Kiel J, Rune G, Richter K, Langnaese K, Masneuf S, Bösl MR, Fischer KD, Krugers HJ, Lipp HP, van Galen E, Kutsche K | title = Dysregulation of Rho GTPases in the αPix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits | journal = Human Molecular Genetics | volume = 21| issue = 2 | pages = 268-286 | date = January 2012 | pmid = 21989057 | pmc = | doi = 10.1093/hmg/ddr457 | access-date = }}</ref> [[Immune_system#Adaptive_immune_system |immune]] [[T-cell]] migration and maturation defects,<ref name=”pmid24591366”>{{cite journal | vauthors = Korthals M, Schilling K, Reichardt P, Mamula D, Schlüter T, Steiner M, Langnäse K, Thomas U, Gundelfinger E, Premont RT, Tedford K, Fischer KD | title = αPIX RhoGEF supports positive selection by restraining migration and promoting arrest of thymocytes | journal = Journal of Immunology | volume = 192| issue = 7 | pages = 3228-3238 | date = April 2014 | pmid = 24591366 | pmc = | doi = 10.4049/jimmunol.1302585 | access-date = }}</ref> and [[hearing loss]].<ref name=”pmid30333726”>{{cite journal | vauthors = Zhu C, Cheng C, Wang Y, Muhammad W, Liu S, Zhu W, Shao B, Zhang Z, Yan X, He Q, Xu Z, Yu C, Qian X, Lu L, Zhang S, Zhang Y, Xiong W, Gao X, Xu Z, Chai R | title = Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice | journal = Frontiers in Molecular Neuroscience | volume = 11| issue = | pages = 362 | date = October 2018 | pmid = 30333726 | pmc = 6176010 | doi = 10.3389/fnmol.2018.00362 | access-date = }}</ref>

== Interactions ==
αPIX has been reported to interact with over 40 proteins.<ref name=”pmid27182061”/><ref name="BioGRID">{{cite web | title = ARHGEF6 Result Summary | url = https://thebiogrid.org/114847| accessdate = }}</ref>

Major interacting proteins include:
* Itself, or the highly-related [[ARHGEF7 |ARHGEF7/βPIX]] via a trimeric coiled-coil interaction.
* [[GIT1]] or [[GIT2]] dimers via GIT-binding domain.
* [[p21-activated kinases | p21-activated kinases (PAKs) 1, 2 and 3]] via SH3 domain.
* [[c-Cbl]] via SH3 domain.
* [[Rho family of GTPases | Rho family GTP-binding protein family]] members [[Rac1]] and [[Cdc42]], activated via DHPH [[RhoGEF domain]].

== See also ==
* [[Rho family of GTPases]]
* [[Scaffold protein]]
* [[Guanine nucleotide exchange factor]]
* [[X-linked intellectual disability]]


==References==
==References==
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==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | vauthors=Nomura N, Miyajima N, Sazuka T |title=Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line KG-1 |journal=DNA Res. |volume=1 |issue= 1 |pages= 27–35 |year= 1995 |pmid= 7584026 |doi=10.1093/dnares/1.1.27 |display-authors=etal}}
*{{cite journal | vauthors=Nomura N, Miyajima N, Sazuka T |title=Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line KG-1 (supplement) |journal=DNA Res. |volume=1 |issue= 1 |pages= 47–56 |year= 1995 |pmid= 7584028 |doi=10.1093/dnares/1.1.47 |display-authors=etal}}
*{{cite journal | vauthors=Ebinu JO, Bottorff DA, Chan EY |title=RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs |journal=Science |volume=280 |issue= 5366 |pages= 1082–6 |year= 1998 |pmid= 9582122 |doi=10.1126/science.280.5366.1082 |display-authors=etal}}
*{{cite journal | vauthors=Yntema HG, Hamel BC, Smits AP |title=Localisation of a gene for non-specific X linked mental retardation (MRX46) to Xq25-q26 |journal=J. Med. Genet. |volume=35 |issue= 10 |pages= 801–5 |year= 1999 |pmid= 9783701 |doi=10.1136/jmg.35.10.801 | pmc=1051453 |display-authors=etal}}
*{{cite journal | vauthors=Yntema HG, Hamel BC, Smits AP |title=Localisation of a gene for non-specific X linked mental retardation (MRX46) to Xq25-q26 |journal=J. Med. Genet. |volume=35 |issue= 10 |pages= 801–5 |year= 1999 |pmid= 9783701 |doi=10.1136/jmg.35.10.801 | pmc=1051453 |display-authors=etal}}
*{{cite journal | vauthors=Yoshii S, Tanaka M, Otsuki Y |title=alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase |journal=Oncogene |volume=18 |issue= 41 |pages= 5680–90 |year= 1999 |pmid= 10523848 |doi= 10.1038/sj.onc.1202936 |display-authors=etal}}
*{{cite journal | vauthors=Yoshii S, Tanaka M, Otsuki Y |title=alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase |journal=Oncogene |volume=18 |issue= 41 |pages= 5680–90 |year= 1999 |pmid= 10523848 |doi= 10.1038/sj.onc.1202936 |display-authors=etal}}
*{{cite journal | vauthors=Brown A, Wang X, Sawai E, Cheng-Mayer C |title=Activation of the PAK-related kinase by human immunodeficiency virus type 1 Nef in primary human peripheral blood lymphocytes and macrophages leads to phosphorylation of a PIX-p95 complex |journal=J. Virol. |volume=73 |issue= 12 |pages= 9899–907 |year= 1999 |pmid= 10559302 |doi= | pmc=113039 }}
*{{cite journal | vauthors=Brown A, Wang X, Sawai E, Cheng-Mayer C |title=Activation of the PAK-related kinase by human immunodeficiency virus type 1 Nef in primary human peripheral blood lymphocytes and macrophages leads to phosphorylation of a PIX-p95 complex |journal=J. Virol. |volume=73 |issue= 12 |pages= 9899–907 |year= 1999 |pmid= 10559302 |doi= | pmc=113039 }}
*{{cite journal | vauthors=Premont RT, Claing A, Vitale N |title=The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing |journal=J. Biol. Chem. |volume=275 |issue= 29 |pages= 22373–80 |year= 2000 |pmid= 10896954 |doi=10.1074/jbc.275.29.22373 |display-authors=etal}}
*{{cite journal | vauthors=Premont RT, Claing A, Vitale N |title=The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing |journal=J. Biol. Chem. |volume=275 |issue= 29 |pages= 22373–80 |year= 2000 |pmid= 10896954 |doi=10.1074/jbc.275.29.22373 |display-authors=etal}}
*{{cite journal | vauthors=Kutsche K, Yntema H, Brandt A |title=Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation |journal=Nat. Genet. |volume=26 |issue= 2 |pages= 247–50 |year= 2000 |pmid= 11017088 |doi= 10.1038/80002 |display-authors=etal}}
*{{cite journal | vauthors=Lower KM, Gecz J |title=Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Börjeson-Forssman-Lehmann syndrome and MRX27 |journal=Am. J. Med. Genet. |volume=100 |issue= 1 |pages= 43–8 |year= 2001 |pmid= 11337747 |doi=10.1002/ajmg.1189 }}
*{{cite journal | vauthors=Lower KM, Gecz J |title=Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Börjeson-Forssman-Lehmann syndrome and MRX27 |journal=Am. J. Med. Genet. |volume=100 |issue= 1 |pages= 43–8 |year= 2001 |pmid= 11337747 |doi=10.1002/ajmg.1189 }}
*{{cite journal | vauthors=Yoshii S, Tanaka M, Otsuki Y |title=Involvement of alpha-PAK-interacting exchange factor in the PAK1-c-Jun NH(2)-terminal kinase 1 activation and apoptosis induced by benzo[a]pyrene |journal=Mol. Cell. Biol. |volume=21 |issue= 20 |pages= 6796–807 |year= 2001 |pmid= 11564864 |doi= 10.1128/MCB.21.20.6796-6807.2001 | pmc=99857 |display-authors=etal}}
*{{cite journal | vauthors=Yoshii S, Tanaka M, Otsuki Y |title=Involvement of alpha-PAK-interacting exchange factor in the PAK1-c-Jun NH(2)-terminal kinase 1 activation and apoptosis induced by benzo[a]pyrene |journal=Mol. Cell. Biol. |volume=21 |issue= 20 |pages= 6796–807 |year= 2001 |pmid= 11564864 |doi= 10.1128/MCB.21.20.6796-6807.2001 | pmc=99857 |display-authors=etal}}
*{{cite journal | vauthors=Vikis HG, Li W, Guan KL |title=The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding |journal=Genes Dev. |volume=16 |issue= 7 |pages= 836–45 |year= 2002 |pmid= 11937491 |doi= 10.1101/gad.966402 | pmc=186329 }}
*{{cite journal | vauthors=Vikis HG, Li W, Guan KL |title=The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding |journal=Genes Dev. |volume=16 |issue= 7 |pages= 836–45 |year= 2002 |pmid= 11937491 |doi= 10.1101/gad.966402 | pmc=186329 }}
*{{cite journal | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |display-authors=etal}}
⚫
*{{cite journal | vauthors=Rosenberger G, Jantke I, Gal A, Kutsche K |title=Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling |journal=Hum. Mol. Genet. |volume=12 |issue= 2 |pages= 155–67 |year= 2003 |pmid= 12499396 |doi=10.1093/hmg/ddg019 }}
*{{cite journal | vauthors=Flanders JA, Feng Q, Bagrodia S |title=The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins |journal=FEBS Lett. |volume=550 |issue= 1–3 |pages= 119–23 |year= 2003 |pmid= 12935897 |doi=10.1016/S0014-5793(03)00853-6 |display-authors=etal}}
*{{cite journal | vauthors=Flanders JA, Feng Q, Bagrodia S |title=The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins |journal=FEBS Lett. |volume=550 |issue= 1–3 |pages= 119–23 |year= 2003 |pmid= 12935897 |doi=10.1016/S0014-5793(03)00853-6 |display-authors=etal}}
*{{cite journal | vauthors=Brill LM, Salomon AR, Ficarro SB |title=Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry |journal=Anal. Chem. |volume=76 |issue= 10 |pages= 2763–72 |year= 2004 |pmid= 15144186 |doi= 10.1021/ac035352d |display-authors=etal}}
*{{cite journal | vauthors=Brill LM, Salomon AR, Ficarro SB |title=Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry |journal=Anal. Chem. |volume=76 |issue= 10 |pages= 2763–72 |year= 2004 |pmid= 15144186 |doi= 10.1021/ac035352d |display-authors=etal}}
*{{cite journal | vauthors=Djordjevic T, Hess J, Herkert O |title=Rac regulates thrombin-induced tissue factor expression in pulmonary artery smooth muscle cells involving the nuclear factor-kappaB pathway |journal=Antioxid. Redox Signal. |volume=6 |issue= 4 |pages= 713–20 |year= 2005 |pmid= 15242552 |doi= 10.1089/1523086041361703 |display-authors=etal}}
*{{cite journal | vauthors=Beausoleil SA, Jedrychowski M, Schwartz D |title=Large-scale characterization of HeLa cell nuclear phosphoproteins |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130–5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 | pmc=514446 |display-authors=etal}}
*{{cite journal | vauthors=Beausoleil SA, Jedrychowski M, Schwartz D |title=Large-scale characterization of HeLa cell nuclear phosphoproteins |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130–5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 | pmc=514446 |display-authors=etal}}
*{{cite journal | vauthors=Jin J, Smith FD, Stark C |title=Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization |journal=Curr. Biol. |volume=14 |issue= 16 |pages= 1436–50 |year= 2004 |pmid= 15324660 |doi= 10.1016/j.cub.2004.07.051 |display-authors=etal}}
*{{cite journal | vauthors=Jin J, Smith FD, Stark C |title=Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization |journal=Curr. Biol. |volume=14 |issue= 16 |pages= 1436–50 |year= 2004 |pmid= 15324660 |doi= 10.1016/j.cub.2004.07.051 |display-authors=etal}}
{{refend}}
{{refend}}
{{PDB Gallery|geneid=9459}}
{{PDB Gallery|geneid=9459}}





Revision as of 19:10, 9 August 2019

ARHGEF6
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesARHGEF6, COOL2, Cool-2, MRX46, PIXA, alpha-PIX, alphaPIX, Rac/Cdc42 guanine nucleotide exchange factor 6
External IDsOMIM: 300267; MGI: 1920591; HomoloGene: 3561; GeneCards: ARHGEF6; OMA:ARHGEF6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9459

73341

Ensembl

ENSG00000129675

ENSMUSG00000031133

UniProt

Q15052

Q8K4I3

RefSeq (mRNA)

NM_001306177
NM_004840

NM_152801
NM_001358573

RefSeq (protein)

NP_001293106
NP_004831

Location (UCSC)Chr X: 136.67 – 136.78 MbChr X: 57.23 – 57.34 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Rho guanine nucleotide exchange factor 6 is a protein that, in humans, is encoded by the ARHGEF6 gene.[5][6][7]

ARHGEF6 is commonly known as the p21-activated protein kinase exchange factor alpha (alpha-PIX or αPIX), because it was identified by binding to p21-activated kinase (PAK) and also contains a guanine nucleotide exchange factor domain.[6]

Domains and functions

αPIX is a multidomain protein that functions both as a signaling scaffold protein and as an enzyme.[8] αPIX shares this domain structure and signaling function with the highly similar ARHGEF7/βPIX protein. αPIX contains a central DH/PH RhoGEF domain that functions as a guanine nucleotide exchange factor (GEF) for small GTPases of the Rho family, and specifically Rac and Cdc42.[6] Like other GEFs, αPIX can promote both release of GDP from an inactive small GTP-binding protein and binding of GTP to promote its activation. Signaling scaffolds bind to specific partners to promote efficient signal transduction by arranging sequential elements of a pathway near each other to facilitate interaction/information transfer, and also by holding these partner protein complexes in specific locations within the cell to promote local or regional signaling. In the case of αPIX, its SH3 domain binds to partner proteins with appropriate polyproline motifs, and particularly to group I p21-activated kinases (PAKs) (PAK1, PAK2 and PAK3).[6] PAK is bound to the αPIX SH3 domain in the inactive state, and activated Rac1 or Cdc42 binding to this PAK stimulates its protein kinase activity leading to downstream target protein phosphorylation; since αPIX can activate the “p21’’ small GTPases Rac1 or Cdc42 through its GEF activity, this αPIX/PAK/Rac complex exemplifies a scaffolding function. Structurally, αPIX assembles as a trimer through its carboxyl-terminal coiled-coil domain, and further interacts with dimers of GIT1 or GIT2 through a nearby GIT-binding domain to form oligomeric GIT-PIX complexes.[8] Through this GIT-PIX complex, the scaffolding function of αPIX is amplified by also being able to hold GIT partners in proximity to αPIX partners. αPIX contains an amino-terminal Calponin Homology (CH) domain whose functions remain relatively poorly defined, but interacts with parvin/affixin family proteins. [9][8]

Because the ARHGEF6 gene is located on the X chromosome so that males have only one copy, mutations in this gene in humans can cause X-chromosome-linked non-specific intellectual disability, [10] as can mutations affecting its binding partner PAK3 whose gene is also located on the X chromosome.[11] In animal models, loss of ARHGEF6 gene function is associated with neuronal synapse defects,[12] immune T-cell migration and maturation defects,[13] and hearing loss.[14]

Interactions

αPIX has been reported to interact with over 40 proteins.[8][15]

Major interacting proteins include:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000129675 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031133 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S (Dec 1995). "Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1 (supplement)". DNA Res. 1 (5): 251–62. doi:10.1093/dnares/1.5.251. PMID 7584048.
  6. ^ a b c d Manser E, Loo TH, Koh CG, Zhao ZS, Chen XQ, Tan L, Tan I, Leung T, Lim L (Jul 1998). "PAK kinases are directly coupled to the PIX family of nucleotide exchange factors". Mol Cell. 1 (2): 183–92. doi:10.1016/S1097-2765(00)80019-2. PMID 9659915.
  7. ^ "Entrez Gene: ARHGEF6 Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6".
  8. ^ a b c d Zhou W, Li X, Premont RT (May 2016). "Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT-PIX complexes". Journal of Cell Science. 129 (10): 1963–1974. doi:10.1242/jcs.179465. PMC 6518221. PMID 27182061.
  9. ^ Rosenberger G, Jantke I, Gal A, Kutsche K (2003). "Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling". Human Molecular Genetics. 12 (2): 155–167. doi:10.1093/hmg/ddg019. PMID 12499396.
  10. ^ Kutsche K, Yntema H, Brandt A, Jantke I, Nothwang HG, Orth U, Boavida MG, David D, Chelly J, Fryns JP, Moraine C, Ropers HH, Hamel BC, van Bokhoven H, Gal A (2000). "Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation". Nature Genetics. 26 (2): 247–250. doi:10.1038/80002. PMID 11017088.
  11. ^ Allen KM, Gleeson JG, Bagrodia S, Partington MW, MacMillan JC, Cerione RA, Mulley JC, Walsh CA (September 1998). "PAK3 mutation in nonsyndromic X-linked mental retardation". Nature Genetics. 20 (1): 25–30. doi:10.1038/1675. PMID 9731525.
  12. ^ Ramakers GJ, Wolfer D, Rosenberger G, Kuchenbecker K, Kreienkamp HJ, Prange-Kiel J, Rune G, Richter K, Langnaese K, Masneuf S, Bösl MR, Fischer KD, Krugers HJ, Lipp HP, van Galen E, Kutsche K (January 2012). "Dysregulation of Rho GTPases in the αPix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits". Human Molecular Genetics. 21 (2): 268–286. doi:10.1093/hmg/ddr457. PMID 21989057.
  13. ^ Korthals M, Schilling K, Reichardt P, Mamula D, Schlüter T, Steiner M, Langnäse K, Thomas U, Gundelfinger E, Premont RT, Tedford K, Fischer KD (April 2014). "αPIX RhoGEF supports positive selection by restraining migration and promoting arrest of thymocytes". Journal of Immunology. 192 (7): 3228–3238. doi:10.4049/jimmunol.1302585. PMID 24591366.
  14. ^ Zhu C, Cheng C, Wang Y, Muhammad W, Liu S, Zhu W, Shao B, Zhang Z, Yan X, He Q, Xu Z, Yu C, Qian X, Lu L, Zhang S, Zhang Y, Xiong W, Gao X, Xu Z, Chai R (October 2018). "Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice". Frontiers in Molecular Neuroscience. 11: 362. doi:10.3389/fnmol.2018.00362. PMC 6176010. PMID 30333726.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ "ARHGEF6 Result Summary".

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