Full text data of ARFGEF2
ARFGEF2
(ARFGEP2, BIG2)
[Confidence: low (only semi-automatic identification from reviews)]
Brefeldin A-inhibited guanine nucleotide-exchange protein 2; Brefeldin A-inhibited GEP 2 (ADP-ribosylation factor guanine nucleotide-exchange factor 2)
Brefeldin A-inhibited guanine nucleotide-exchange protein 2; Brefeldin A-inhibited GEP 2 (ADP-ribosylation factor guanine nucleotide-exchange factor 2)
UniProt
Q9Y6D5
ID BIG2_HUMAN Reviewed; 1785 AA.
AC Q9Y6D5; Q5TFT9; Q9NTS1;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 06-MAR-2007, sequence version 3.
DT 22-JAN-2014, entry version 121.
DE RecName: Full=Brefeldin A-inhibited guanine nucleotide-exchange protein 2;
DE Short=Brefeldin A-inhibited GEP 2;
DE AltName: Full=ADP-ribosylation factor guanine nucleotide-exchange factor 2;
GN Name=ARFGEF2; Synonyms=ARFGEP2, BIG2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=10212200; DOI=10.1074/jbc.274.18.12308;
RA Togawa A., Morinaga N., Ogasawara M., Moss J., Vaughan M.;
RT "Purification and cloning of a brefeldin A-inhibited guanine
RT nucleotide-exchange protein for ADP-ribosylation factors.";
RL J. Biol. Chem. 274:12308-12315(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [3]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH BIG1.
RX PubMed=10716990; DOI=10.1073/pnas.97.6.2567;
RA Yamaji R., Adamik R., Takeda K., Togawa A., Pacheco-Rodriguez G.,
RA Ferrans V.J., Moss J., Vaughan M.;
RT "Identification and localization of two brefeldin A-inhibited guanine
RT nucleotide-exchange proteins for ADP-ribosylation factors in a
RT macromolecular complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:2567-2572(2000).
RN [4]
RP FUNCTION, AND MUTAGENESIS OF GLU-738.
RX PubMed=12051703; DOI=10.1016/S0006-291X(02)00456-4;
RA Shinotsuka C., Waguri S., Wakasugi M., Uchiyama Y., Nakayama K.;
RT "Dominant-negative mutant of BIG2, an ARF-guanine nucleotide exchange
RT factor, specifically affects membrane trafficking from the trans-Golgi
RT network through inhibiting membrane association of AP-1 and GGA coat
RT proteins.";
RL Biochem. Biophys. Res. Commun. 294:254-260(2002).
RN [5]
RP FUNCTION, INTERACTION WITH PRKAR1A; PRKAR2A; PRKAR1B AND PRKAR2B, AND
RP SUBCELLULAR LOCATION.
RX PubMed=12571360; DOI=10.1073/pnas.0337678100;
RA Li H., Adamik R., Pacheco-Rodriguez G., Moss J., Vaughan M.;
RT "Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited
RT guanine nucleotide-exchange protein 2 (BIG2).";
RL Proc. Natl. Acad. Sci. U.S.A. 100:1627-1632(2003).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-738.
RX PubMed=15385626; DOI=10.1091/mbc.E04-05-0388;
RA Shin H.W., Morinaga N., Noda M., Nakayama K.;
RT "BIG2, a guanine nucleotide exchange factor for ADP-ribosylation
RT factors: its localization to recycling endosomes and implication in
RT the endosome integrity.";
RL Mol. Biol. Cell 15:5283-5294(2004).
RN [7]
RP INTERACTION WITH EXOC7, AND SUBCELLULAR LOCATION.
RX PubMed=15705715; DOI=10.1073/pnas.0409871102;
RA Xu K.F., Shen X., Li H., Pacheco-Rodriguez G., Moss J., Vaughan M.;
RT "Interaction of BIG2, a brefeldin A-inhibited guanine nucleotide-
RT exchange protein, with exocyst protein Exo70.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:2784-2789(2005).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218; SER-227; SER-1525
RP AND SER-1528, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH MYCBP.
RX PubMed=16866877; DOI=10.1111/j.1365-2443.2006.00991.x;
RA Ishizaki R., Shin H.W., Iguchi-Ariga S.M., Ariga H., Nakayama K.;
RT "AMY-1 (associate of Myc-1) localization to the trans-Golgi network
RT through interacting with BIG2, a guanine-nucleotide exchange factor
RT for ADP-ribosylation factors.";
RL Genes Cells 11:949-959(2006).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16477018; DOI=10.1073/pnas.0510599103;
RA Shen X., Xu K.F., Fan Q., Pacheco-Rodriguez G., Moss J., Vaughan M.;
RT "Association of brefeldin A-inhibited guanine nucleotide-exchange
RT protein 2 (BIG2) with recycling endosomes during transferrin uptake.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:2635-2640(2006).
RN [11]
RP FUNCTION, AND INTERACTION WITH TNFRSF1A.
RX PubMed=17276987; DOI=10.1074/jbc.M607122200;
RA Islam A., Shen X., Hiroi T., Moss J., Vaughan M., Levine S.J.;
RT "The brefeldin A-inhibited guanine nucleotide-exchange protein, BIG2,
RT regulates the constitutive release of TNFR1 exosome-like vesicles.";
RL J. Biol. Chem. 282:9591-9599(2007).
RN [12]
RP SUBUNIT.
RX PubMed=17640864; DOI=10.1074/jbc.M705525200;
RA Ramaen O., Joubert A., Simister P., Belgareh-Touze N.,
RA Olivares-Sanchez M.C., Zeeh J.C., Chantalat S., Golinelli-Cohen M.P.,
RA Jackson C.L., Biou V., Cherfils J.;
RT "Interactions between conserved domains within homodimers in the BIG1,
RT BIG2, and GBF1 Arf guanine nucleotide exchange factors.";
RL J. Biol. Chem. 282:28834-28842(2007).
RN [13]
RP PHOSPHORYLATION, AND INTERACTION WITH PPP1CC.
RX PubMed=17360629; DOI=10.1073/pnas.0611696104;
RA Kuroda F., Moss J., Vaughan M.;
RT "Regulation of brefeldin A-inhibited guanine nucleotide-exchange
RT protein 1 (BIG1) and BIG2 activity via PKA and protein phosphatase
RT 1gamma.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:3201-3206(2007).
RN [14]
RP FUNCTION, INTERACTION WITH PRKAR2B, AND MUTAGENESIS OF VAL-289 AND
RP VAL-534.
RX PubMed=18625701; DOI=10.1074/jbc.M804966200;
RA Islam A., Jones H., Hiroi T., Lam J., Zhang J., Moss J., Vaughan M.,
RA Levine S.J.;
RT "cAMP-dependent protein kinase A (PKA) signaling induces TNFR1
RT exosome-like vesicle release via anchoring of PKA regulatory subunit
RT RIIbeta to BIG2.";
RL J. Biol. Chem. 283:25364-25371(2008).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218; SER-227; SER-1528
RP AND SER-1782, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-614, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1528, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [19]
RP INTERACTION WITH PDE3A.
RX PubMed=19332778; DOI=10.1073/pnas.0901558106;
RA Puxeddu E., Uhart M., Li C.C., Ahmad F., Pacheco-Rodriguez G.,
RA Manganiello V.C., Moss J., Vaughan M.;
RT "Interaction of phosphodiesterase 3A with brefeldin A-inhibited
RT guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1
RT activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:6158-6163(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-227; SER-277; SER-1525
RP AND SER-1528, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [21]
RP FUNCTION.
RX PubMed=20360857; DOI=10.1371/journal.pone.0009898;
RA Boal F., Stephens D.J.;
RT "Specific functions of BIG1 and BIG2 in endomembrane organization.";
RL PLoS ONE 5:E9898-E9898(2010).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218; SER-227 AND
RP SER-1528, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218 AND SER-227, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [25]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [26]
RP VARIANT PVNH2 LYS-209.
RX PubMed=14647276; DOI=10.1038/ng1276;
RA Sheen V.L., Ganesh V.S., Topcu M., Sebire G., Bodell A., Hill R.S.,
RA Grant P.E., Shugart Y.Y., Imitola J., Khoury S.J., Guerrini R.,
RA Walsh C.A.;
RT "Mutations in ARFGEF2 implicate vesicle trafficking in neural
RT progenitor proliferation and migration in the human cerebral cortex.";
RL Nat. Genet. 36:69-76(2004).
RN [27]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-794.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [28]
RP VARIANT GLN-802.
RX PubMed=23033978; DOI=10.1056/NEJMoa1206524;
RA de Ligt J., Willemsen M.H., van Bon B.W., Kleefstra T., Yntema H.G.,
RA Kroes T., Vulto-van Silfhout A.T., Koolen D.A., de Vries P.,
RA Gilissen C., del Rosario M., Hoischen A., Scheffer H., de Vries B.B.,
RA Brunner H.G., Veltman J.A., Vissers L.E.;
RT "Diagnostic exome sequencing in persons with severe intellectual
RT disability.";
RL N. Engl. J. Med. 367:1921-1929(2012).
CC -!- FUNCTION: Promotes guanine-nucleotide exchange on ARF1 and ARF3
CC and to a lower extend on ARF5 and ARF6. Promotes the activation of
CC ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in
CC the regulation of Golgi vesicular transport. Required for the
CC integrity of the endosomal compartment. Involved in trafficking
CC from the trans-Golgi network (TGN) to endosomes and is required
CC for membrane association of the AP-1 complex and GGA1. Seems to be
CC involved in recycling of the transferrin receptor from recycling
CC endosomes to the plasma membrane. Probably is involved in the exit
CC of GABA(A) receptors from the endoplasmic reticulum. Involved in
CC constitutive release of tumor necrosis factor receptor 1 via
CC exosome-like vesicles; the function seems to involve PKA and
CC specifically PRKAR2B. Proposed to act as A kinase-anchoring
CC protein (AKAP) and may mediate crosstalk between Arf and PKA
CC pathways.
CC -!- ENZYME REGULATION: Inhibited by brefeldin A.
CC -!- SUBUNIT: Homodimer (Probable). Interacts with BIG1; both proteins
CC are probably part of the same or very similar macromolecular
CC complexes. Interacts with PRKAR1A, PRKAR2A, PRKAR1B, PRKAR2B,
CC PPP1CC, PDE3A, TNFRSF1A, MYCBP and EXOC7. Interacts with GABRB1,
CC GABRB2 and GABRB3 (By similarity).
CC -!- INTERACTION:
CC Q9Y6D6:ARFGEF1; NbExp=3; IntAct=EBI-2837511, EBI-1044254;
CC Q9UPT5-1:EXOC7; NbExp=4; IntAct=EBI-2837511, EBI-6251402;
CC Q99417:MYCBP; NbExp=5; IntAct=EBI-2837511, EBI-716185;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane. Golgi apparatus.
CC Cytoplasm, perinuclear region. Golgi apparatus, trans-Golgi
CC network (By similarity). Endosome (By similarity). Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome. Cell
CC projection, dendrite (By similarity). Cytoplasmic vesicle (By
CC similarity). Cell junction, synapse (By similarity). Cytoplasm,
CC cytoskeleton (By similarity). Note=Translocates from cytoplasm to
CC membranes upon cAMP treatment. Localized in recycling endosomes.
CC -!- TISSUE SPECIFICITY: Expressed in placenta, lung, heart, brain,
CC kidney and pancreas.
CC -!- PTM: In vitro phosphorylated by PKA reducing its GEF activity and
CC dephosphorylated by phosphatase PP1.
CC -!- DISEASE: Periventricular nodular heterotopia 2 (PVNH2)
CC [MIM:608097]: A developmental disorder characterized by the
CC presence of periventricular nodules of cerebral gray matter,
CC resulting from a failure of neurons to migrate normally from the
CC lateral ventricular proliferative zone, where they are formed, to
CC the cerebral cortex. PVNH2 is an autosomal recessive form
CC characterized by microcephaly (small brain), severe developmental
CC delay and recurrent infections. No anomalies extrinsic to the
CC central nervous system, such as dysmorphic features or grossly
CC abnormal endocrine or other conditions, are associated with PVNH2.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Contains 1 SEC7 domain.
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DR EMBL; AF084521; AAD38428.1; -; mRNA.
DR EMBL; AL049537; CAI19320.1; -; Genomic_DNA.
DR EMBL; AL121903; CAI19320.1; JOINED; Genomic_DNA.
DR EMBL; AL121903; CAI19614.1; -; Genomic_DNA.
DR EMBL; AL049537; CAI19614.1; JOINED; Genomic_DNA.
DR RefSeq; NP_006411.2; NM_006420.2.
DR UniGene; Hs.62578; -.
DR PDB; 3L8N; X-ray; 2.86 A; A=635-836.
DR PDB; 3SWV; X-ray; 3.00 A; A=635-836.
DR PDBsum; 3L8N; -.
DR PDBsum; 3SWV; -.
DR ProteinModelPortal; Q9Y6D5; -.
DR SMR; Q9Y6D5; 637-828.
DR DIP; DIP-48794N; -.
DR IntAct; Q9Y6D5; 12.
DR MINT; MINT-1200143; -.
DR STRING; 9606.ENSP00000360985; -.
DR PhosphoSite; Q9Y6D5; -.
DR DMDM; 146329988; -.
DR PaxDb; Q9Y6D5; -.
DR PRIDE; Q9Y6D5; -.
DR Ensembl; ENST00000371917; ENSP00000360985; ENSG00000124198.
DR GeneID; 10564; -.
DR KEGG; hsa:10564; -.
DR UCSC; uc002xtx.4; human.
DR CTD; 10564; -.
DR GeneCards; GC20P047538; -.
DR H-InvDB; HIX0015895; -.
DR HGNC; HGNC:15853; ARFGEF2.
DR HPA; CAB026382; -.
DR HPA; HPA026078; -.
DR MIM; 605371; gene.
DR MIM; 608097; phenotype.
DR neXtProt; NX_Q9Y6D5; -.
DR Orphanet; 98892; Periventricular nodular heterotopia.
DR PharmGKB; PA24945; -.
DR eggNOG; COG5307; -.
DR HOGENOM; HOG000181045; -.
DR HOVERGEN; HBG004846; -.
DR InParanoid; Q9Y6D5; -.
DR OMA; EVWDETC; -.
DR OrthoDB; EOG7QVM1S; -.
DR PhylomeDB; Q9Y6D5; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR ChiTaRS; ARFGEF2; human.
DR GeneWiki; ARFGEF2; -.
DR GenomeRNAi; 10564; -.
DR NextBio; 40093; -.
DR PRO; PR:Q9Y6D5; -.
DR ArrayExpress; Q9Y6D5; -.
DR Bgee; Q9Y6D5; -.
DR CleanEx; HS_ARFGEF2; -.
DR Genevestigator; Q9Y6D5; -.
DR GO; GO:0032279; C:asymmetric synapse; ISS:UniProtKB.
DR GO; GO:0005879; C:axonemal microtubule; ISS:UniProtKB.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0005815; C:microtubule organizing center; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
DR GO; GO:0032280; C:symmetric synapse; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0005086; F:ARF guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0050811; F:GABA receptor binding; ISS:UniProtKB.
DR GO; GO:0034237; F:protein kinase A regulatory subunit binding; IDA:UniProtKB.
DR GO; GO:0010256; P:endomembrane system organization; IMP:UniProtKB.
DR GO; GO:0007032; P:endosome organization; IMP:UniProtKB.
DR GO; GO:0006887; P:exocytosis; TAS:ProtInc.
DR GO; GO:0006893; P:Golgi to plasma membrane transport; IMP:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:MGI.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0001881; P:receptor recycling; IDA:UniProtKB.
DR GO; GO:0032012; P:regulation of ARF protein signal transduction; IEA:InterPro.
DR Gene3D; 1.10.1000.11; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR015403; DUF1981_Sec7_assoc.
DR InterPro; IPR023394; Sec7_alpha_orthog.
DR InterPro; IPR000904; Sec7_dom.
DR Pfam; PF09324; DUF1981; 1.
DR Pfam; PF01369; Sec7; 1.
DR SMART; SM00222; Sec7; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR SUPFAM; SSF48425; SSF48425; 1.
DR PROSITE; PS50190; SEC7; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell junction; Cell projection;
KW Complete proteome; Cytoplasm; Cytoplasmic vesicle; Cytoskeleton;
KW Disease mutation; Endosome; Golgi apparatus;
KW Guanine-nucleotide releasing factor; Membrane; Phosphoprotein;
KW Polymorphism; Protein transport; Reference proteome; Synapse;
KW Transport.
FT CHAIN 1 1785 Brefeldin A-inhibited guanine nucleotide-
FT exchange protein 2.
FT /FTId=PRO_0000120208.
FT DOMAIN 654 785 SEC7.
FT REGION 2 224 DCB; DCB:DCB domain and DCB:HUS domain
FT interaction.
FT REGION 508 528 HUS; DCB:HUS domain interaction.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 218 218 Phosphoserine.
FT MOD_RES 227 227 Phosphoserine.
FT MOD_RES 277 277 Phosphoserine.
FT MOD_RES 614 614 Phosphoserine.
FT MOD_RES 616 616 Phosphothreonine (By similarity).
FT MOD_RES 1525 1525 Phosphoserine.
FT MOD_RES 1528 1528 Phosphoserine.
FT MOD_RES 1782 1782 Phosphoserine.
FT VARIANT 209 209 E -> K (in PVNH2; dbSNP:rs28937880).
FT /FTId=VAR_037438.
FT VARIANT 527 527 A -> V (in dbSNP:rs6063343).
FT /FTId=VAR_028750.
FT VARIANT 794 794 K -> E (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036156.
FT VARIANT 802 802 R -> Q.
FT /FTId=VAR_069404.
FT MUTAGEN 289 289 V->W: Abolishes interaction with PRKAR2B
FT and impairs TNFRSF1A release.
FT MUTAGEN 534 534 V->W: Abolishes interaction with PRKAR2B
FT and impairs TNFRSF1A release.
FT MUTAGEN 738 738 E->K: Disturbs membrane organization at
FT the TGN, impairs association of the AP-1
FT complex and GGA1 with the TGN membranes.
FT CONFLICT 207 207 E -> R (in Ref. 1; AAD38428).
FT CONFLICT 962 962 E -> K (in Ref. 1; AAD38428).
FT CONFLICT 1049 1049 D -> N (in Ref. 1; AAD38428).
FT CONFLICT 1763 1763 G -> S (in Ref. 1; AAD38428).
FT HELIX 641 643
FT TURN 644 648
FT HELIX 649 654
FT HELIX 658 667
FT TURN 674 678
FT HELIX 679 682
FT HELIX 690 694
FT TURN 695 698
FT TURN 702 705
FT HELIX 706 712
FT HELIX 723 729
FT HELIX 739 753
FT HELIX 766 777
FT TURN 778 782
FT TURN 796 798
FT STRAND 799 801
FT STRAND 804 808
FT HELIX 812 822
SQ SEQUENCE 1785 AA; 202038 MW; D419106E5BAF19C2 CRC64;
MQESQTKSMF VSRALEKILA DKEVKRPQHS QLRRACQVAL DEIKAEIEKQ RLGTAAPPKA
NFIEADKYFL PFELACQSKS PRVVSTSLDC LQKLIAYGHI TGNAPDSGAP GKRLIDRIVE
TICSCFQGPQ TDEGVQLQII KALLTAVTSP HIEIHEGTIL QTVRTCYNIY LASKNLINQT
TAKATLTQML NVIFTRMENQ VLQEARELEK PIQSKPQSPV IQAAAVSPKF VRLKHSQAQS
KPTTPEKTDL TNGEHARSDS GKVSTENGDA PRERGSSLSG TDDGAQEVVK DILEDVVTSA
IKEAAEKHGL TEPERVLGEL ECQECAIPPG VDENSQTNGI ADDRQSLSSA DNLESDAQGH
QVAARFSHVL QKDAFLVFRS LCKLSMKPLG EGPPDPKSHE LRSKVVSLQL LLSVLQNAGP
VFRTHEMFIN AIKQYLCVAL SKNGVSSVPD VFELSLAIFL TLLSNFKMHL KMQIEVFFKE
IFLNILETST SSFEHRWMVI QTLTRICADA QCVVDIYVNY DCDLNAANIF ERLVNDLSKI
AQGRSGHELG MTPLQELSLR KKGLECLVSI LKCMVEWSKD LYVNPNHQTS LGQERLTDQE
IGDGKGLDMA RRCSVTSMES TVSSGTQTTV QDDPEQFEVI KQQKEIIEHG IELFNKKPKR
GIQFLQEQGM LGTSVEDIAQ FLHQEERLDS TQVGDFLGDS ARFNKEVMYA YVDQLDFCEK
EFVSALRTFL EGFRLPGEAQ KIDRLMEKFA ARYIECNQGQ TLFASADTAY VLAYSIIMLT
TDLHSPQVKN KMTKEQYIKM NRGINDSKDL PEEYLSSIYE EIEGKKIAMK ETKELTIATK
STKQNVASEK QRRLLYNLEM EQMAKTAKAL MEAVSHAKAP FTSATHLDHV RPMFKLVWTP
LLAAYSIGLQ NCDDTEVASL CLEGIRCAIR IACIFGMQLE RDAYVQALAR FSLLTASSSI
TEMKQKNIDT IKTLITVAHT DGNYLGNSWH EILKCISQLE LAQLIGTGVK TRYLSGSGRE
REGSLKGHTL AGEEFMGLGL GNLVSGGVDK RQMASFQESV GETSSQSVVV AVDRIFTGST
RLDGNAIVDF VRWLCAVSMD ELASPHHPRM FSLQKIVEIS YYNMNRIRLQ WSRIWHVIGD
HFNKVGCNPN EDVAIFAVDS LRQLSMKFLE KGELANFRFQ KDFLRPFEHI MKKNRSPTIR
DMAIRCIAQM VNSQAANIRS GWKNIFAVFH QAASDHDGNI VELAFQTTCH IVTTIFQHHF
PAAIDSFQDA VKCLSEFACN AAFPDTSMEA IRLIRFCGKY VSERPRVLQE YTSDDMNVAP
GDRVWVRGWF PILFELSCII NRCKLDVRTR GLTVMFEIMK SYGHTFEKHW WQDLFRIVFR
IFDNMKLPEQ LSEKSEWMTT TCNHALYAIC DVFTQFYEAL NEVLLSDVFA QLQWCVKQDN
EQLARSGTNC LENLVISNGE KFSPEVWDET CNCMLDIFKT TIPHVLLTWR PVGMEEDSSE
KHLDVDLDRQ SLSSIDKNPS ERGQSQLSNP TDDSWKGRPY ANQKLFASLL IKCVVQLELI
QTIDNIVFYP ATSKKEDAEH MVAAQQDTLD ADIHIETEDQ GMYKYMSSQH LFKLLDCLQE
SHSFSKAFNS NYEQRTVLWR AGFKGKSKPN LLKQETSSLA CCLRILFRMY VDENRRDSWE
EIQQRLLTVC SEALAYFITV NSESHREAWT SLLLLLLTKT LKINDEKFKA HASMYYPYLC
EIMQFDLIPE LRAVLRKFFL RIGVVYKIWI PEEPSQVPAA LSPVW
//
ID BIG2_HUMAN Reviewed; 1785 AA.
AC Q9Y6D5; Q5TFT9; Q9NTS1;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 06-MAR-2007, sequence version 3.
DT 22-JAN-2014, entry version 121.
DE RecName: Full=Brefeldin A-inhibited guanine nucleotide-exchange protein 2;
DE Short=Brefeldin A-inhibited GEP 2;
DE AltName: Full=ADP-ribosylation factor guanine nucleotide-exchange factor 2;
GN Name=ARFGEF2; Synonyms=ARFGEP2, BIG2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=10212200; DOI=10.1074/jbc.274.18.12308;
RA Togawa A., Morinaga N., Ogasawara M., Moss J., Vaughan M.;
RT "Purification and cloning of a brefeldin A-inhibited guanine
RT nucleotide-exchange protein for ADP-ribosylation factors.";
RL J. Biol. Chem. 274:12308-12315(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [3]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH BIG1.
RX PubMed=10716990; DOI=10.1073/pnas.97.6.2567;
RA Yamaji R., Adamik R., Takeda K., Togawa A., Pacheco-Rodriguez G.,
RA Ferrans V.J., Moss J., Vaughan M.;
RT "Identification and localization of two brefeldin A-inhibited guanine
RT nucleotide-exchange proteins for ADP-ribosylation factors in a
RT macromolecular complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:2567-2572(2000).
RN [4]
RP FUNCTION, AND MUTAGENESIS OF GLU-738.
RX PubMed=12051703; DOI=10.1016/S0006-291X(02)00456-4;
RA Shinotsuka C., Waguri S., Wakasugi M., Uchiyama Y., Nakayama K.;
RT "Dominant-negative mutant of BIG2, an ARF-guanine nucleotide exchange
RT factor, specifically affects membrane trafficking from the trans-Golgi
RT network through inhibiting membrane association of AP-1 and GGA coat
RT proteins.";
RL Biochem. Biophys. Res. Commun. 294:254-260(2002).
RN [5]
RP FUNCTION, INTERACTION WITH PRKAR1A; PRKAR2A; PRKAR1B AND PRKAR2B, AND
RP SUBCELLULAR LOCATION.
RX PubMed=12571360; DOI=10.1073/pnas.0337678100;
RA Li H., Adamik R., Pacheco-Rodriguez G., Moss J., Vaughan M.;
RT "Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited
RT guanine nucleotide-exchange protein 2 (BIG2).";
RL Proc. Natl. Acad. Sci. U.S.A. 100:1627-1632(2003).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-738.
RX PubMed=15385626; DOI=10.1091/mbc.E04-05-0388;
RA Shin H.W., Morinaga N., Noda M., Nakayama K.;
RT "BIG2, a guanine nucleotide exchange factor for ADP-ribosylation
RT factors: its localization to recycling endosomes and implication in
RT the endosome integrity.";
RL Mol. Biol. Cell 15:5283-5294(2004).
RN [7]
RP INTERACTION WITH EXOC7, AND SUBCELLULAR LOCATION.
RX PubMed=15705715; DOI=10.1073/pnas.0409871102;
RA Xu K.F., Shen X., Li H., Pacheco-Rodriguez G., Moss J., Vaughan M.;
RT "Interaction of BIG2, a brefeldin A-inhibited guanine nucleotide-
RT exchange protein, with exocyst protein Exo70.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:2784-2789(2005).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218; SER-227; SER-1525
RP AND SER-1528, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH MYCBP.
RX PubMed=16866877; DOI=10.1111/j.1365-2443.2006.00991.x;
RA Ishizaki R., Shin H.W., Iguchi-Ariga S.M., Ariga H., Nakayama K.;
RT "AMY-1 (associate of Myc-1) localization to the trans-Golgi network
RT through interacting with BIG2, a guanine-nucleotide exchange factor
RT for ADP-ribosylation factors.";
RL Genes Cells 11:949-959(2006).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16477018; DOI=10.1073/pnas.0510599103;
RA Shen X., Xu K.F., Fan Q., Pacheco-Rodriguez G., Moss J., Vaughan M.;
RT "Association of brefeldin A-inhibited guanine nucleotide-exchange
RT protein 2 (BIG2) with recycling endosomes during transferrin uptake.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:2635-2640(2006).
RN [11]
RP FUNCTION, AND INTERACTION WITH TNFRSF1A.
RX PubMed=17276987; DOI=10.1074/jbc.M607122200;
RA Islam A., Shen X., Hiroi T., Moss J., Vaughan M., Levine S.J.;
RT "The brefeldin A-inhibited guanine nucleotide-exchange protein, BIG2,
RT regulates the constitutive release of TNFR1 exosome-like vesicles.";
RL J. Biol. Chem. 282:9591-9599(2007).
RN [12]
RP SUBUNIT.
RX PubMed=17640864; DOI=10.1074/jbc.M705525200;
RA Ramaen O., Joubert A., Simister P., Belgareh-Touze N.,
RA Olivares-Sanchez M.C., Zeeh J.C., Chantalat S., Golinelli-Cohen M.P.,
RA Jackson C.L., Biou V., Cherfils J.;
RT "Interactions between conserved domains within homodimers in the BIG1,
RT BIG2, and GBF1 Arf guanine nucleotide exchange factors.";
RL J. Biol. Chem. 282:28834-28842(2007).
RN [13]
RP PHOSPHORYLATION, AND INTERACTION WITH PPP1CC.
RX PubMed=17360629; DOI=10.1073/pnas.0611696104;
RA Kuroda F., Moss J., Vaughan M.;
RT "Regulation of brefeldin A-inhibited guanine nucleotide-exchange
RT protein 1 (BIG1) and BIG2 activity via PKA and protein phosphatase
RT 1gamma.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:3201-3206(2007).
RN [14]
RP FUNCTION, INTERACTION WITH PRKAR2B, AND MUTAGENESIS OF VAL-289 AND
RP VAL-534.
RX PubMed=18625701; DOI=10.1074/jbc.M804966200;
RA Islam A., Jones H., Hiroi T., Lam J., Zhang J., Moss J., Vaughan M.,
RA Levine S.J.;
RT "cAMP-dependent protein kinase A (PKA) signaling induces TNFR1
RT exosome-like vesicle release via anchoring of PKA regulatory subunit
RT RIIbeta to BIG2.";
RL J. Biol. Chem. 283:25364-25371(2008).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218; SER-227; SER-1528
RP AND SER-1782, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-614, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1528, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [19]
RP INTERACTION WITH PDE3A.
RX PubMed=19332778; DOI=10.1073/pnas.0901558106;
RA Puxeddu E., Uhart M., Li C.C., Ahmad F., Pacheco-Rodriguez G.,
RA Manganiello V.C., Moss J., Vaughan M.;
RT "Interaction of phosphodiesterase 3A with brefeldin A-inhibited
RT guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1
RT activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:6158-6163(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-227; SER-277; SER-1525
RP AND SER-1528, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [21]
RP FUNCTION.
RX PubMed=20360857; DOI=10.1371/journal.pone.0009898;
RA Boal F., Stephens D.J.;
RT "Specific functions of BIG1 and BIG2 in endomembrane organization.";
RL PLoS ONE 5:E9898-E9898(2010).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218; SER-227 AND
RP SER-1528, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218 AND SER-227, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [25]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [26]
RP VARIANT PVNH2 LYS-209.
RX PubMed=14647276; DOI=10.1038/ng1276;
RA Sheen V.L., Ganesh V.S., Topcu M., Sebire G., Bodell A., Hill R.S.,
RA Grant P.E., Shugart Y.Y., Imitola J., Khoury S.J., Guerrini R.,
RA Walsh C.A.;
RT "Mutations in ARFGEF2 implicate vesicle trafficking in neural
RT progenitor proliferation and migration in the human cerebral cortex.";
RL Nat. Genet. 36:69-76(2004).
RN [27]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-794.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [28]
RP VARIANT GLN-802.
RX PubMed=23033978; DOI=10.1056/NEJMoa1206524;
RA de Ligt J., Willemsen M.H., van Bon B.W., Kleefstra T., Yntema H.G.,
RA Kroes T., Vulto-van Silfhout A.T., Koolen D.A., de Vries P.,
RA Gilissen C., del Rosario M., Hoischen A., Scheffer H., de Vries B.B.,
RA Brunner H.G., Veltman J.A., Vissers L.E.;
RT "Diagnostic exome sequencing in persons with severe intellectual
RT disability.";
RL N. Engl. J. Med. 367:1921-1929(2012).
CC -!- FUNCTION: Promotes guanine-nucleotide exchange on ARF1 and ARF3
CC and to a lower extend on ARF5 and ARF6. Promotes the activation of
CC ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in
CC the regulation of Golgi vesicular transport. Required for the
CC integrity of the endosomal compartment. Involved in trafficking
CC from the trans-Golgi network (TGN) to endosomes and is required
CC for membrane association of the AP-1 complex and GGA1. Seems to be
CC involved in recycling of the transferrin receptor from recycling
CC endosomes to the plasma membrane. Probably is involved in the exit
CC of GABA(A) receptors from the endoplasmic reticulum. Involved in
CC constitutive release of tumor necrosis factor receptor 1 via
CC exosome-like vesicles; the function seems to involve PKA and
CC specifically PRKAR2B. Proposed to act as A kinase-anchoring
CC protein (AKAP) and may mediate crosstalk between Arf and PKA
CC pathways.
CC -!- ENZYME REGULATION: Inhibited by brefeldin A.
CC -!- SUBUNIT: Homodimer (Probable). Interacts with BIG1; both proteins
CC are probably part of the same or very similar macromolecular
CC complexes. Interacts with PRKAR1A, PRKAR2A, PRKAR1B, PRKAR2B,
CC PPP1CC, PDE3A, TNFRSF1A, MYCBP and EXOC7. Interacts with GABRB1,
CC GABRB2 and GABRB3 (By similarity).
CC -!- INTERACTION:
CC Q9Y6D6:ARFGEF1; NbExp=3; IntAct=EBI-2837511, EBI-1044254;
CC Q9UPT5-1:EXOC7; NbExp=4; IntAct=EBI-2837511, EBI-6251402;
CC Q99417:MYCBP; NbExp=5; IntAct=EBI-2837511, EBI-716185;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane. Golgi apparatus.
CC Cytoplasm, perinuclear region. Golgi apparatus, trans-Golgi
CC network (By similarity). Endosome (By similarity). Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome. Cell
CC projection, dendrite (By similarity). Cytoplasmic vesicle (By
CC similarity). Cell junction, synapse (By similarity). Cytoplasm,
CC cytoskeleton (By similarity). Note=Translocates from cytoplasm to
CC membranes upon cAMP treatment. Localized in recycling endosomes.
CC -!- TISSUE SPECIFICITY: Expressed in placenta, lung, heart, brain,
CC kidney and pancreas.
CC -!- PTM: In vitro phosphorylated by PKA reducing its GEF activity and
CC dephosphorylated by phosphatase PP1.
CC -!- DISEASE: Periventricular nodular heterotopia 2 (PVNH2)
CC [MIM:608097]: A developmental disorder characterized by the
CC presence of periventricular nodules of cerebral gray matter,
CC resulting from a failure of neurons to migrate normally from the
CC lateral ventricular proliferative zone, where they are formed, to
CC the cerebral cortex. PVNH2 is an autosomal recessive form
CC characterized by microcephaly (small brain), severe developmental
CC delay and recurrent infections. No anomalies extrinsic to the
CC central nervous system, such as dysmorphic features or grossly
CC abnormal endocrine or other conditions, are associated with PVNH2.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Contains 1 SEC7 domain.
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DR EMBL; AF084521; AAD38428.1; -; mRNA.
DR EMBL; AL049537; CAI19320.1; -; Genomic_DNA.
DR EMBL; AL121903; CAI19320.1; JOINED; Genomic_DNA.
DR EMBL; AL121903; CAI19614.1; -; Genomic_DNA.
DR EMBL; AL049537; CAI19614.1; JOINED; Genomic_DNA.
DR RefSeq; NP_006411.2; NM_006420.2.
DR UniGene; Hs.62578; -.
DR PDB; 3L8N; X-ray; 2.86 A; A=635-836.
DR PDB; 3SWV; X-ray; 3.00 A; A=635-836.
DR PDBsum; 3L8N; -.
DR PDBsum; 3SWV; -.
DR ProteinModelPortal; Q9Y6D5; -.
DR SMR; Q9Y6D5; 637-828.
DR DIP; DIP-48794N; -.
DR IntAct; Q9Y6D5; 12.
DR MINT; MINT-1200143; -.
DR STRING; 9606.ENSP00000360985; -.
DR PhosphoSite; Q9Y6D5; -.
DR DMDM; 146329988; -.
DR PaxDb; Q9Y6D5; -.
DR PRIDE; Q9Y6D5; -.
DR Ensembl; ENST00000371917; ENSP00000360985; ENSG00000124198.
DR GeneID; 10564; -.
DR KEGG; hsa:10564; -.
DR UCSC; uc002xtx.4; human.
DR CTD; 10564; -.
DR GeneCards; GC20P047538; -.
DR H-InvDB; HIX0015895; -.
DR HGNC; HGNC:15853; ARFGEF2.
DR HPA; CAB026382; -.
DR HPA; HPA026078; -.
DR MIM; 605371; gene.
DR MIM; 608097; phenotype.
DR neXtProt; NX_Q9Y6D5; -.
DR Orphanet; 98892; Periventricular nodular heterotopia.
DR PharmGKB; PA24945; -.
DR eggNOG; COG5307; -.
DR HOGENOM; HOG000181045; -.
DR HOVERGEN; HBG004846; -.
DR InParanoid; Q9Y6D5; -.
DR OMA; EVWDETC; -.
DR OrthoDB; EOG7QVM1S; -.
DR PhylomeDB; Q9Y6D5; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR ChiTaRS; ARFGEF2; human.
DR GeneWiki; ARFGEF2; -.
DR GenomeRNAi; 10564; -.
DR NextBio; 40093; -.
DR PRO; PR:Q9Y6D5; -.
DR ArrayExpress; Q9Y6D5; -.
DR Bgee; Q9Y6D5; -.
DR CleanEx; HS_ARFGEF2; -.
DR Genevestigator; Q9Y6D5; -.
DR GO; GO:0032279; C:asymmetric synapse; ISS:UniProtKB.
DR GO; GO:0005879; C:axonemal microtubule; ISS:UniProtKB.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0005815; C:microtubule organizing center; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
DR GO; GO:0032280; C:symmetric synapse; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0005086; F:ARF guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0050811; F:GABA receptor binding; ISS:UniProtKB.
DR GO; GO:0034237; F:protein kinase A regulatory subunit binding; IDA:UniProtKB.
DR GO; GO:0010256; P:endomembrane system organization; IMP:UniProtKB.
DR GO; GO:0007032; P:endosome organization; IMP:UniProtKB.
DR GO; GO:0006887; P:exocytosis; TAS:ProtInc.
DR GO; GO:0006893; P:Golgi to plasma membrane transport; IMP:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:MGI.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0001881; P:receptor recycling; IDA:UniProtKB.
DR GO; GO:0032012; P:regulation of ARF protein signal transduction; IEA:InterPro.
DR Gene3D; 1.10.1000.11; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR015403; DUF1981_Sec7_assoc.
DR InterPro; IPR023394; Sec7_alpha_orthog.
DR InterPro; IPR000904; Sec7_dom.
DR Pfam; PF09324; DUF1981; 1.
DR Pfam; PF01369; Sec7; 1.
DR SMART; SM00222; Sec7; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR SUPFAM; SSF48425; SSF48425; 1.
DR PROSITE; PS50190; SEC7; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell junction; Cell projection;
KW Complete proteome; Cytoplasm; Cytoplasmic vesicle; Cytoskeleton;
KW Disease mutation; Endosome; Golgi apparatus;
KW Guanine-nucleotide releasing factor; Membrane; Phosphoprotein;
KW Polymorphism; Protein transport; Reference proteome; Synapse;
KW Transport.
FT CHAIN 1 1785 Brefeldin A-inhibited guanine nucleotide-
FT exchange protein 2.
FT /FTId=PRO_0000120208.
FT DOMAIN 654 785 SEC7.
FT REGION 2 224 DCB; DCB:DCB domain and DCB:HUS domain
FT interaction.
FT REGION 508 528 HUS; DCB:HUS domain interaction.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 218 218 Phosphoserine.
FT MOD_RES 227 227 Phosphoserine.
FT MOD_RES 277 277 Phosphoserine.
FT MOD_RES 614 614 Phosphoserine.
FT MOD_RES 616 616 Phosphothreonine (By similarity).
FT MOD_RES 1525 1525 Phosphoserine.
FT MOD_RES 1528 1528 Phosphoserine.
FT MOD_RES 1782 1782 Phosphoserine.
FT VARIANT 209 209 E -> K (in PVNH2; dbSNP:rs28937880).
FT /FTId=VAR_037438.
FT VARIANT 527 527 A -> V (in dbSNP:rs6063343).
FT /FTId=VAR_028750.
FT VARIANT 794 794 K -> E (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036156.
FT VARIANT 802 802 R -> Q.
FT /FTId=VAR_069404.
FT MUTAGEN 289 289 V->W: Abolishes interaction with PRKAR2B
FT and impairs TNFRSF1A release.
FT MUTAGEN 534 534 V->W: Abolishes interaction with PRKAR2B
FT and impairs TNFRSF1A release.
FT MUTAGEN 738 738 E->K: Disturbs membrane organization at
FT the TGN, impairs association of the AP-1
FT complex and GGA1 with the TGN membranes.
FT CONFLICT 207 207 E -> R (in Ref. 1; AAD38428).
FT CONFLICT 962 962 E -> K (in Ref. 1; AAD38428).
FT CONFLICT 1049 1049 D -> N (in Ref. 1; AAD38428).
FT CONFLICT 1763 1763 G -> S (in Ref. 1; AAD38428).
FT HELIX 641 643
FT TURN 644 648
FT HELIX 649 654
FT HELIX 658 667
FT TURN 674 678
FT HELIX 679 682
FT HELIX 690 694
FT TURN 695 698
FT TURN 702 705
FT HELIX 706 712
FT HELIX 723 729
FT HELIX 739 753
FT HELIX 766 777
FT TURN 778 782
FT TURN 796 798
FT STRAND 799 801
FT STRAND 804 808
FT HELIX 812 822
SQ SEQUENCE 1785 AA; 202038 MW; D419106E5BAF19C2 CRC64;
MQESQTKSMF VSRALEKILA DKEVKRPQHS QLRRACQVAL DEIKAEIEKQ RLGTAAPPKA
NFIEADKYFL PFELACQSKS PRVVSTSLDC LQKLIAYGHI TGNAPDSGAP GKRLIDRIVE
TICSCFQGPQ TDEGVQLQII KALLTAVTSP HIEIHEGTIL QTVRTCYNIY LASKNLINQT
TAKATLTQML NVIFTRMENQ VLQEARELEK PIQSKPQSPV IQAAAVSPKF VRLKHSQAQS
KPTTPEKTDL TNGEHARSDS GKVSTENGDA PRERGSSLSG TDDGAQEVVK DILEDVVTSA
IKEAAEKHGL TEPERVLGEL ECQECAIPPG VDENSQTNGI ADDRQSLSSA DNLESDAQGH
QVAARFSHVL QKDAFLVFRS LCKLSMKPLG EGPPDPKSHE LRSKVVSLQL LLSVLQNAGP
VFRTHEMFIN AIKQYLCVAL SKNGVSSVPD VFELSLAIFL TLLSNFKMHL KMQIEVFFKE
IFLNILETST SSFEHRWMVI QTLTRICADA QCVVDIYVNY DCDLNAANIF ERLVNDLSKI
AQGRSGHELG MTPLQELSLR KKGLECLVSI LKCMVEWSKD LYVNPNHQTS LGQERLTDQE
IGDGKGLDMA RRCSVTSMES TVSSGTQTTV QDDPEQFEVI KQQKEIIEHG IELFNKKPKR
GIQFLQEQGM LGTSVEDIAQ FLHQEERLDS TQVGDFLGDS ARFNKEVMYA YVDQLDFCEK
EFVSALRTFL EGFRLPGEAQ KIDRLMEKFA ARYIECNQGQ TLFASADTAY VLAYSIIMLT
TDLHSPQVKN KMTKEQYIKM NRGINDSKDL PEEYLSSIYE EIEGKKIAMK ETKELTIATK
STKQNVASEK QRRLLYNLEM EQMAKTAKAL MEAVSHAKAP FTSATHLDHV RPMFKLVWTP
LLAAYSIGLQ NCDDTEVASL CLEGIRCAIR IACIFGMQLE RDAYVQALAR FSLLTASSSI
TEMKQKNIDT IKTLITVAHT DGNYLGNSWH EILKCISQLE LAQLIGTGVK TRYLSGSGRE
REGSLKGHTL AGEEFMGLGL GNLVSGGVDK RQMASFQESV GETSSQSVVV AVDRIFTGST
RLDGNAIVDF VRWLCAVSMD ELASPHHPRM FSLQKIVEIS YYNMNRIRLQ WSRIWHVIGD
HFNKVGCNPN EDVAIFAVDS LRQLSMKFLE KGELANFRFQ KDFLRPFEHI MKKNRSPTIR
DMAIRCIAQM VNSQAANIRS GWKNIFAVFH QAASDHDGNI VELAFQTTCH IVTTIFQHHF
PAAIDSFQDA VKCLSEFACN AAFPDTSMEA IRLIRFCGKY VSERPRVLQE YTSDDMNVAP
GDRVWVRGWF PILFELSCII NRCKLDVRTR GLTVMFEIMK SYGHTFEKHW WQDLFRIVFR
IFDNMKLPEQ LSEKSEWMTT TCNHALYAIC DVFTQFYEAL NEVLLSDVFA QLQWCVKQDN
EQLARSGTNC LENLVISNGE KFSPEVWDET CNCMLDIFKT TIPHVLLTWR PVGMEEDSSE
KHLDVDLDRQ SLSSIDKNPS ERGQSQLSNP TDDSWKGRPY ANQKLFASLL IKCVVQLELI
QTIDNIVFYP ATSKKEDAEH MVAAQQDTLD ADIHIETEDQ GMYKYMSSQH LFKLLDCLQE
SHSFSKAFNS NYEQRTVLWR AGFKGKSKPN LLKQETSSLA CCLRILFRMY VDENRRDSWE
EIQQRLLTVC SEALAYFITV NSESHREAWT SLLLLLLTKT LKINDEKFKA HASMYYPYLC
EIMQFDLIPE LRAVLRKFFL RIGVVYKIWI PEEPSQVPAA LSPVW
//
MIM
605371
*RECORD*
*FIELD* NO
605371
*FIELD* TI
*605371 ADP-RIBOSYLATION FACTOR GUANINE NUCLEOTIDE EXCHANGE FACTOR 2; ARFGEF2
;;BREFELDIN A-INHIBITED GUANINE NUCLEOTIDE EXCHANGE PROTEIN 2; BIG2
read more*FIELD* TX
For general information about brefeldin A (BFA)-inhibited guanine
nucleotide exchange proteins, see BIG1 (604141).
CLONING
Togawa et al. (1999) isolated BIG2 from a human frontal cortex cDNA
library. BIG2 encodes a protein of 1,785 amino acids containing a Sec7
domain characteristic of other ADP-ribosylation factor (ARF) guanine
nucleotide exchange proteins. BIG2 shares 74% overall amino acid
identity with BIG1 and 90% identity within the Sec7 domain. By Northern
blot analysis, Togawa et al. (1999) detected a 9.4-kb BIG2 transcript in
placenta, lung, heart, brain, kidney, and pancreas.
By Northern blot analysis, Sheen et al. (2004) found that mouse Arfgef2
mRNA levels are highest during embryonic periods of ongoing neuronal
proliferation and migration, and by in situ hybridization, they found
that the mRNA is widely distributed throughout the embryonic CNS.
GENE FUNCTION
Togawa et al. (1999) synthesized a 20-kD recombinant BIG2 that
accelerated GTP binding by ARFs and was inhibited by BFA.
Sheen et al. (2004) found that the BIG2 protein is required for vesicle
and membrane trafficking from the trans-Golgi network. Inhibition of
BIG2 by BFA, or by a dominant-negative ARFGEF2 cDNA, decreased cell
proliferation in vitro, suggesting a cell-autonomous regulation of
neural expansion. Inhibition of BIG2 also disturbed the intracellular
localization of such molecules as E-cadherin (192090) and beta-catenin
(116806) by preventing their transport from the Golgi apparatus to the
cell surface. The findings showed that vesicle trafficking is an
important regulator of proliferation and migration during human cerebral
cortical development.
Kuroda et al. (2007) showed that elevated cAMP in HepG2 cells caused PKA
(see PRKACA; 601639)-catalyzed phosphorylation and nuclear accumulation
of BIG1, but not BIG2. Phosphorylation of BIG1 or BIG2 by PKA was
associated with decreased BIG1 or BIG2 GEP activity, which could be
restored by dephosphorylation by PP1-gamma (PPP1CC; 176914). Kuroda et
al. (2007) concluded that cAMP, PKA, and PP1-gamma regulate vesicular
traffic via their effects on the phosphorylation status of BIG1 and
BIG2.
MAPPING
Using somatic cell hybrid analysis, Togawa et al. (1999) mapped the BIG2
gene to chromosome 20.
MOLECULAR GENETICS
Autosomal recessive periventricular heterotopia with microcephaly
(ARPHM; 608097) is a severe malformation of the cerebral cortex,
characterized by severe developmental delay and recurrent infections
(Sheen et al., 2003). By an initial genomewide screen at 10-cM intervals
in 2 Turkish families with ARPHM, Sheen et al. (2004) identified shared
homozygosity at a single locus on 20q11.21-q13.2, which they refined by
further marker analysis. They sequenced several candidate genes in the
minimal linkage region, and in each family they identified a homozygous
mutation in the ARFGEF2 gene (605371.0001 and 605371.0002).
In 5 members of a consanguineous Palestinian family with periventricular
heterotopia with microcephaly, Banne et al. (2013) identified a
homozygous mutation in the ARFGEF2 gene (605371.0003). The mutation was
found by homozygosity mapping combined with whole-exome sequencing.
*FIELD* AV
.0001
PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, GLU209LYS
In affected members of a consanguineous Turkish family with autosomal
recessive periventricular heterotopia with microcephaly (ARPHM; 608097),
Sheen et al. (2004) identified a 625G-A transition in exon 6 of the
ARFGEF2 gene, which produced a nonconservative amino acid substitution,
glu209 to lys (E209K).
.0002
PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, PRO81GLN, VAL83LEU, 249delA
In affected members of a consanguineous Turkish family with autosomal
recessive periventricular heterotopia with microcephaly (608097), Sheen
et al. (2004) identified a complex homozygous mutation in exon 3 of the
ARFGEF2 gene, consisting of the nucleotide substitutions 242C-A and
247G-T and the deletion 249delA. These nucleotide changes caused amino
acid substitutions pro81 to gln (P81Q) and val83 to leu (V83L) and a
translational frameshift at amino acid residue 84, resulting in
premature termination of translation after 30 additional abnormal amino
acids.
.0003
PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, IVS14DS, G-A, +1
In 5 members of a consanguineous Palestinian family with periventricular
heterotopia with microcephaly (608097), Banne et al. (2013) identified a
homozygous G-to-A transition in intron 14 of the ARFGEF2 gene
(c.1958+1G-A), resulting in the elimination of 44 nucleotides of the
patients' cDNA. The mutation was found by homozygosity mapping combined
with whole-exome sequencing and segregated with the disorder in the
family. It was not present in the dbSNP (build 132) database or among
in-house database variants. The patients had severely delayed
psychomotor development, microcephaly, and infantile seizures associated
with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West
syndrome. Brain MRI showed periventricular heterotopia and thin corpus
callosum. No other organ systems were affected.
*FIELD* RF
1. Banne, E.; Atawneh, O.; Henneke, M.; Brockmann, K.; Gartner, J.;
Elpeleg, O.; Edvardson, S.: West syndrome, microcephaly, grey matter
heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2
mutation. J. Med. Genet. 50: 772-775, 2013.
2. Kuroda, F.; Moss, J.; Vaughan, M.: Regulation of brefeldin A-inhibited
guanine nucleotide-exchange protein 1 (BIG1) and BIG2 activity via
PKA and protein phosphatase 1-gamma. Proc. Nat. Acad. Sci. 104:
3201-3206, 2007.
3. Sheen, V. L.; Ganesh, V. S.; Topcu, M.; Sebire, G.; Bodell, A.;
Hill, R. S.; Grant, P. E.; Shugart, Y. Y.; Imitola, J.; Khoury, S.
J.; Guerrini, R.; Walsh, C. A.: Mutations in ARFGEF2 implicate vesicle
trafficking in neural progenitor proliferation and migration in the
human cerebral cortex. Nature Genet. 36: 69-76, 2004.
4. Sheen, V. L.; Topcu, M.; Berkovic, S.; Yalnizoglu, D.; Blatt, I.;
Bodell, A.; Hill, R. S.; Ganesh, V. S.; Cherry, T. J.; Shugart, Y.
Y.; Walsh, C. A.: Autosomal recessive form of periventricular heterotopia. Neurology 60:
1108-1112, 2003.
5. Togawa, A.; Morinaga, N.; Ogasawara, M.; Moss, J.; Vaughan, M.
: Purification and cloning of a brefeldin A-inhibited guanine nucleotide-exchange
protein for ADP-ribosylation factors. J. Biol. Chem. 274: 12308-12315,
1999.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/3/2013
Patricia A. Hartz - updated: 4/13/2007
Victor A. McKusick - updated: 1/2/2004
*FIELD* CD
Dawn Watkins-Chow: 10/26/2000
*FIELD* ED
carol: 12/05/2013
carol: 12/5/2013
ckniffin: 12/3/2013
mgross: 4/16/2007
terry: 4/13/2007
wwang: 9/21/2006
tkritzer: 1/9/2004
tkritzer: 1/7/2004
terry: 1/2/2004
joanna: 12/22/2003
carol: 10/30/2000
*RECORD*
*FIELD* NO
605371
*FIELD* TI
*605371 ADP-RIBOSYLATION FACTOR GUANINE NUCLEOTIDE EXCHANGE FACTOR 2; ARFGEF2
;;BREFELDIN A-INHIBITED GUANINE NUCLEOTIDE EXCHANGE PROTEIN 2; BIG2
read more*FIELD* TX
For general information about brefeldin A (BFA)-inhibited guanine
nucleotide exchange proteins, see BIG1 (604141).
CLONING
Togawa et al. (1999) isolated BIG2 from a human frontal cortex cDNA
library. BIG2 encodes a protein of 1,785 amino acids containing a Sec7
domain characteristic of other ADP-ribosylation factor (ARF) guanine
nucleotide exchange proteins. BIG2 shares 74% overall amino acid
identity with BIG1 and 90% identity within the Sec7 domain. By Northern
blot analysis, Togawa et al. (1999) detected a 9.4-kb BIG2 transcript in
placenta, lung, heart, brain, kidney, and pancreas.
By Northern blot analysis, Sheen et al. (2004) found that mouse Arfgef2
mRNA levels are highest during embryonic periods of ongoing neuronal
proliferation and migration, and by in situ hybridization, they found
that the mRNA is widely distributed throughout the embryonic CNS.
GENE FUNCTION
Togawa et al. (1999) synthesized a 20-kD recombinant BIG2 that
accelerated GTP binding by ARFs and was inhibited by BFA.
Sheen et al. (2004) found that the BIG2 protein is required for vesicle
and membrane trafficking from the trans-Golgi network. Inhibition of
BIG2 by BFA, or by a dominant-negative ARFGEF2 cDNA, decreased cell
proliferation in vitro, suggesting a cell-autonomous regulation of
neural expansion. Inhibition of BIG2 also disturbed the intracellular
localization of such molecules as E-cadherin (192090) and beta-catenin
(116806) by preventing their transport from the Golgi apparatus to the
cell surface. The findings showed that vesicle trafficking is an
important regulator of proliferation and migration during human cerebral
cortical development.
Kuroda et al. (2007) showed that elevated cAMP in HepG2 cells caused PKA
(see PRKACA; 601639)-catalyzed phosphorylation and nuclear accumulation
of BIG1, but not BIG2. Phosphorylation of BIG1 or BIG2 by PKA was
associated with decreased BIG1 or BIG2 GEP activity, which could be
restored by dephosphorylation by PP1-gamma (PPP1CC; 176914). Kuroda et
al. (2007) concluded that cAMP, PKA, and PP1-gamma regulate vesicular
traffic via their effects on the phosphorylation status of BIG1 and
BIG2.
MAPPING
Using somatic cell hybrid analysis, Togawa et al. (1999) mapped the BIG2
gene to chromosome 20.
MOLECULAR GENETICS
Autosomal recessive periventricular heterotopia with microcephaly
(ARPHM; 608097) is a severe malformation of the cerebral cortex,
characterized by severe developmental delay and recurrent infections
(Sheen et al., 2003). By an initial genomewide screen at 10-cM intervals
in 2 Turkish families with ARPHM, Sheen et al. (2004) identified shared
homozygosity at a single locus on 20q11.21-q13.2, which they refined by
further marker analysis. They sequenced several candidate genes in the
minimal linkage region, and in each family they identified a homozygous
mutation in the ARFGEF2 gene (605371.0001 and 605371.0002).
In 5 members of a consanguineous Palestinian family with periventricular
heterotopia with microcephaly, Banne et al. (2013) identified a
homozygous mutation in the ARFGEF2 gene (605371.0003). The mutation was
found by homozygosity mapping combined with whole-exome sequencing.
*FIELD* AV
.0001
PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, GLU209LYS
In affected members of a consanguineous Turkish family with autosomal
recessive periventricular heterotopia with microcephaly (ARPHM; 608097),
Sheen et al. (2004) identified a 625G-A transition in exon 6 of the
ARFGEF2 gene, which produced a nonconservative amino acid substitution,
glu209 to lys (E209K).
.0002
PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, PRO81GLN, VAL83LEU, 249delA
In affected members of a consanguineous Turkish family with autosomal
recessive periventricular heterotopia with microcephaly (608097), Sheen
et al. (2004) identified a complex homozygous mutation in exon 3 of the
ARFGEF2 gene, consisting of the nucleotide substitutions 242C-A and
247G-T and the deletion 249delA. These nucleotide changes caused amino
acid substitutions pro81 to gln (P81Q) and val83 to leu (V83L) and a
translational frameshift at amino acid residue 84, resulting in
premature termination of translation after 30 additional abnormal amino
acids.
.0003
PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE
ARFGEF2, IVS14DS, G-A, +1
In 5 members of a consanguineous Palestinian family with periventricular
heterotopia with microcephaly (608097), Banne et al. (2013) identified a
homozygous G-to-A transition in intron 14 of the ARFGEF2 gene
(c.1958+1G-A), resulting in the elimination of 44 nucleotides of the
patients' cDNA. The mutation was found by homozygosity mapping combined
with whole-exome sequencing and segregated with the disorder in the
family. It was not present in the dbSNP (build 132) database or among
in-house database variants. The patients had severely delayed
psychomotor development, microcephaly, and infantile seizures associated
with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West
syndrome. Brain MRI showed periventricular heterotopia and thin corpus
callosum. No other organ systems were affected.
*FIELD* RF
1. Banne, E.; Atawneh, O.; Henneke, M.; Brockmann, K.; Gartner, J.;
Elpeleg, O.; Edvardson, S.: West syndrome, microcephaly, grey matter
heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2
mutation. J. Med. Genet. 50: 772-775, 2013.
2. Kuroda, F.; Moss, J.; Vaughan, M.: Regulation of brefeldin A-inhibited
guanine nucleotide-exchange protein 1 (BIG1) and BIG2 activity via
PKA and protein phosphatase 1-gamma. Proc. Nat. Acad. Sci. 104:
3201-3206, 2007.
3. Sheen, V. L.; Ganesh, V. S.; Topcu, M.; Sebire, G.; Bodell, A.;
Hill, R. S.; Grant, P. E.; Shugart, Y. Y.; Imitola, J.; Khoury, S.
J.; Guerrini, R.; Walsh, C. A.: Mutations in ARFGEF2 implicate vesicle
trafficking in neural progenitor proliferation and migration in the
human cerebral cortex. Nature Genet. 36: 69-76, 2004.
4. Sheen, V. L.; Topcu, M.; Berkovic, S.; Yalnizoglu, D.; Blatt, I.;
Bodell, A.; Hill, R. S.; Ganesh, V. S.; Cherry, T. J.; Shugart, Y.
Y.; Walsh, C. A.: Autosomal recessive form of periventricular heterotopia. Neurology 60:
1108-1112, 2003.
5. Togawa, A.; Morinaga, N.; Ogasawara, M.; Moss, J.; Vaughan, M.
: Purification and cloning of a brefeldin A-inhibited guanine nucleotide-exchange
protein for ADP-ribosylation factors. J. Biol. Chem. 274: 12308-12315,
1999.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/3/2013
Patricia A. Hartz - updated: 4/13/2007
Victor A. McKusick - updated: 1/2/2004
*FIELD* CD
Dawn Watkins-Chow: 10/26/2000
*FIELD* ED
carol: 12/05/2013
carol: 12/5/2013
ckniffin: 12/3/2013
mgross: 4/16/2007
terry: 4/13/2007
wwang: 9/21/2006
tkritzer: 1/9/2004
tkritzer: 1/7/2004
terry: 1/2/2004
joanna: 12/22/2003
carol: 10/30/2000
MIM
608097
*RECORD*
*FIELD* NO
608097
*FIELD* TI
#608097 PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE;
ARPHM
;;PERIVENTRICULAR NODULAR HETEROTOPIA 2; PVNH2;;
read moreHETEROTOPIA, PERIVENTRICULAR, AUTOSOMAL RECESSIVE
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
periventricular nodular heterotopia with microcephaly (ARPHM) is caused
by homozygous mutation in the ARFGEF2 gene (605371) on chromosome 20q13.
For a phenotypic description and a discussion of genetic heterogeneity
of periventricular heterotopia, see 300049.
CLINICAL FEATURES
Sheen et al. (2003) described 2 consanguineous pedigrees with
periventricular heterotopia suggesting an autosomal recessive
inheritance pattern. Magnetic resonance imaging (MRI) of the brains of
affected individuals revealed periventricular nodules of cerebral gray
matter intensity, typical of the disorder. One of the families was
Turkish with a 2.5-year-old boy and 16-month-old girl affected. The
other family was Israeli of Yemenite ethnicity with a much less severe
neurologic phenotype. In this family, a 41-year-old man and his
60-year-old sister had histories of seizures but were otherwise in good
health. Another sib had a history of seizures but refused MRI and was
considered probably affected. Microsatellite analysis of the pedigrees
suggested no linkage to the FLNA (300017) or FLNB (603381) genes. Sheen
et al. (2003) noted the difference in severity between the 2 families
and suggested that it may be due to genetic heterogeneity.
Sheen et al. (2004) noted that severe developmental delay and recurrent
infections are clinical features of ARPHM. No anomalies extrinsic to the
CNS, such as dysmorphic features or grossly abnormal endocrine or other
conditions, are associated. MRI of the brains of affected individuals
shows notable periventricular heterotopia, resulting from a failure of
neurons to migrate normally from the lateral ventricular proliferative
zone, where they are formed, to the cerebral cortex. Abnormal MRI
signals in subcortical white matter and elsewhere also suggest a delay
in the normal myelination by glial cells.
Banne et al. (2013) reported 5 patients from a consanguineous
Palestinian family who developed infantile spasms accompanied by
hypsarrhythmia between ages 3 and 9 months. The patients had severely
delayed psychomotor development even before onset of seizures, and all
eventually showed severe mental retardation. The features were
consistent with a clinical diagnosis of West syndrome. Other features
included progressive microcephaly (-3 to -5 SD) and severe hypotonia.
Brain MRI showed diffuse periventricular heterotopia with a thin corpus
callosum. No other organ systems were affected.
MAPPING
By an initial genomewide screen at 10-cM intervals in 2 Turkish families
with ARPHM, Sheen et al. (2004) identified shared homozygosity at a
single locus on 20q11.21-q13.2, which they refined by further marker
analysis.
MOLECULAR GENETICS
In affected members of 2 Turkish families with ARPHM, including 1
reported by Sheen et al. (2003), Sheen et al. (2004) identified
homozygous mutations in the ARFGEF2 gene (605371.0001 and 605371.0002).
In 5 members of a consanguineous Palestinian family with periventricular
heterotopia with microcephaly, Banne et al. (2013) identified a
homozygous mutation in the ARFGEF2 gene (605371.0003). The mutation was
found by homozygosity mapping combined with whole-exome sequencing.
*FIELD* RF
1. Banne, E.; Atawneh, O.; Henneke, M.; Brockmann, K.; Gartner, J.;
Elpeleg, O.; Edvardson, S.: West syndrome, microcephaly, grey matter
heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2
mutation. J. Med. Genet. 50: 772-775, 2013.
2. Sheen, V. L.; Ganesh, V. S.; Topcu, M.; Sebire, G.; Bodell, A.;
Hill, R. S.; Grant, P. E.; Shugart, Y. Y.; Imitola, J.; Khoury, S.
J.; Guerrini, R.; Walsh, C. A.: Mutations in ARFGEF2 implicate vesicle
trafficking in neural progenitor proliferation and migration in the
human cerebral cortex. Nature Genet. 36: 69-76, 2004.
3. Sheen, V. L.; Topcu, M.; Berkovic, S.; Yalnizoglu, D.; Blatt, I.;
Bodell, A.; Hill, R. S.; Ganesh, V. S.; Cherry, T. J.; Shugart, Y.
Y.; Walsh, C. A.: Autosomal recessive form of periventricular heterotopia. Neurology 60:
1108-1112, 2003.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive (in some patients)
HEAD AND NECK:
[Head];
Microcephaly, progressive (-3 to -5 SD);
[Eyes];
Poor eye contact
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, severe;
Seizures;
Hypsarrhythmia;
Quadriparesis;
Periventricular nodular heterotopia seen on MRI;
Thin corpus callosum
MISCELLANEOUS:
Onset in infancy
MOLECULAR BASIS:
Caused by mutation in the ADP-ribosylation factor guanine nucleotide
exchange factor 2 gene (ARFGEF2, 605371.0001)
*FIELD* CD
Cassandra L. Kniffin: 12/3/2013
*FIELD* ED
joanna: 01/14/2014
ckniffin: 12/3/2013
*FIELD* CN
Cassandra L. Kniffin - updated: 12/3/2013
Victor A. McKusick - updated: 1/2/2004
*FIELD* CD
Victor A. McKusick: 9/15/2003
*FIELD* ED
carol: 12/05/2013
ckniffin: 12/3/2013
ckniffin: 10/25/2004
tkritzer: 1/7/2004
terry: 1/2/2004
mgross: 9/15/2003
*RECORD*
*FIELD* NO
608097
*FIELD* TI
#608097 PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE;
ARPHM
;;PERIVENTRICULAR NODULAR HETEROTOPIA 2; PVNH2;;
read moreHETEROTOPIA, PERIVENTRICULAR, AUTOSOMAL RECESSIVE
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
periventricular nodular heterotopia with microcephaly (ARPHM) is caused
by homozygous mutation in the ARFGEF2 gene (605371) on chromosome 20q13.
For a phenotypic description and a discussion of genetic heterogeneity
of periventricular heterotopia, see 300049.
CLINICAL FEATURES
Sheen et al. (2003) described 2 consanguineous pedigrees with
periventricular heterotopia suggesting an autosomal recessive
inheritance pattern. Magnetic resonance imaging (MRI) of the brains of
affected individuals revealed periventricular nodules of cerebral gray
matter intensity, typical of the disorder. One of the families was
Turkish with a 2.5-year-old boy and 16-month-old girl affected. The
other family was Israeli of Yemenite ethnicity with a much less severe
neurologic phenotype. In this family, a 41-year-old man and his
60-year-old sister had histories of seizures but were otherwise in good
health. Another sib had a history of seizures but refused MRI and was
considered probably affected. Microsatellite analysis of the pedigrees
suggested no linkage to the FLNA (300017) or FLNB (603381) genes. Sheen
et al. (2003) noted the difference in severity between the 2 families
and suggested that it may be due to genetic heterogeneity.
Sheen et al. (2004) noted that severe developmental delay and recurrent
infections are clinical features of ARPHM. No anomalies extrinsic to the
CNS, such as dysmorphic features or grossly abnormal endocrine or other
conditions, are associated. MRI of the brains of affected individuals
shows notable periventricular heterotopia, resulting from a failure of
neurons to migrate normally from the lateral ventricular proliferative
zone, where they are formed, to the cerebral cortex. Abnormal MRI
signals in subcortical white matter and elsewhere also suggest a delay
in the normal myelination by glial cells.
Banne et al. (2013) reported 5 patients from a consanguineous
Palestinian family who developed infantile spasms accompanied by
hypsarrhythmia between ages 3 and 9 months. The patients had severely
delayed psychomotor development even before onset of seizures, and all
eventually showed severe mental retardation. The features were
consistent with a clinical diagnosis of West syndrome. Other features
included progressive microcephaly (-3 to -5 SD) and severe hypotonia.
Brain MRI showed diffuse periventricular heterotopia with a thin corpus
callosum. No other organ systems were affected.
MAPPING
By an initial genomewide screen at 10-cM intervals in 2 Turkish families
with ARPHM, Sheen et al. (2004) identified shared homozygosity at a
single locus on 20q11.21-q13.2, which they refined by further marker
analysis.
MOLECULAR GENETICS
In affected members of 2 Turkish families with ARPHM, including 1
reported by Sheen et al. (2003), Sheen et al. (2004) identified
homozygous mutations in the ARFGEF2 gene (605371.0001 and 605371.0002).
In 5 members of a consanguineous Palestinian family with periventricular
heterotopia with microcephaly, Banne et al. (2013) identified a
homozygous mutation in the ARFGEF2 gene (605371.0003). The mutation was
found by homozygosity mapping combined with whole-exome sequencing.
*FIELD* RF
1. Banne, E.; Atawneh, O.; Henneke, M.; Brockmann, K.; Gartner, J.;
Elpeleg, O.; Edvardson, S.: West syndrome, microcephaly, grey matter
heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2
mutation. J. Med. Genet. 50: 772-775, 2013.
2. Sheen, V. L.; Ganesh, V. S.; Topcu, M.; Sebire, G.; Bodell, A.;
Hill, R. S.; Grant, P. E.; Shugart, Y. Y.; Imitola, J.; Khoury, S.
J.; Guerrini, R.; Walsh, C. A.: Mutations in ARFGEF2 implicate vesicle
trafficking in neural progenitor proliferation and migration in the
human cerebral cortex. Nature Genet. 36: 69-76, 2004.
3. Sheen, V. L.; Topcu, M.; Berkovic, S.; Yalnizoglu, D.; Blatt, I.;
Bodell, A.; Hill, R. S.; Ganesh, V. S.; Cherry, T. J.; Shugart, Y.
Y.; Walsh, C. A.: Autosomal recessive form of periventricular heterotopia. Neurology 60:
1108-1112, 2003.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive (in some patients)
HEAD AND NECK:
[Head];
Microcephaly, progressive (-3 to -5 SD);
[Eyes];
Poor eye contact
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, severe;
Seizures;
Hypsarrhythmia;
Quadriparesis;
Periventricular nodular heterotopia seen on MRI;
Thin corpus callosum
MISCELLANEOUS:
Onset in infancy
MOLECULAR BASIS:
Caused by mutation in the ADP-ribosylation factor guanine nucleotide
exchange factor 2 gene (ARFGEF2, 605371.0001)
*FIELD* CD
Cassandra L. Kniffin: 12/3/2013
*FIELD* ED
joanna: 01/14/2014
ckniffin: 12/3/2013
*FIELD* CN
Cassandra L. Kniffin - updated: 12/3/2013
Victor A. McKusick - updated: 1/2/2004
*FIELD* CD
Victor A. McKusick: 9/15/2003
*FIELD* ED
carol: 12/05/2013
ckniffin: 12/3/2013
ckniffin: 10/25/2004
tkritzer: 1/7/2004
terry: 1/2/2004
mgross: 9/15/2003