BIG2_HUMAN
ID BIG2_HUMAN Reviewed; 1785 AA.
AC Q9Y6D5; Q5TFT9; Q9NTS1;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2007, sequence version 3.
DT 03-AUG-2022, entry version 193.
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC 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 nucleotide-
RT 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., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., 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., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., 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 ARFGEF1.
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 guanine
RT 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 factors:
RT its localization to recycling endosomes and implication in the endosome
RT 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-exchange
RT 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 AND
RP SER-1528, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT 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 through
RT interacting with BIG2, a guanine-nucleotide exchange factor for ADP-
RT 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 protein 2
RT (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 protein 1
RT (BIG1) and BIG2 activity via PKA and protein phosphatase 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 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 exosome-like
RT vesicle release via anchoring of PKA regulatory subunit 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 AND
RP SER-1782, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-614, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1528, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 guanine
RT nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1 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 AND
RP SER-1528, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 SER-1528,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT 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., Buerckstuemmer T.,
RA 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [25]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [26]
RP INVOLVEMENT IN PVNH2.
RX PubMed=23812912; DOI=10.1136/jmedgenet-2013-101752;
RA Banne E., Atawneh O., Henneke M., Brockmann K., Gaertner J., Elpeleg O.,
RA Edvardson S.;
RT "West syndrome, microcephaly, grey matter heterotopia and hypoplasia of
RT corpus callosum due to a novel ARFGEF2 mutation.";
RL J. Med. Genet. 50:772-775(2013).
RN [27]
RP INVOLVEMENT IN PVNH2, AND 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., Walsh C.A.;
RT "Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor
RT proliferation and migration in the human cerebral cortex.";
RL Nat. Genet. 36:69-76(2004).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-227; THR-244; SER-277;
RP SER-349; SER-1511; SER-1525 AND SER-1528, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-214; SER-218; SER-227 AND
RP SER-700, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [30]
RP INVOLVEMENT IN PVNH2.
RX PubMed=25160555; DOI=10.1016/j.pediatrneurol.2014.05.008;
RA Bardon-Cancho E.J., Munoz-Jimenez L., Vazquez-Lopez M., Ruiz-Martin Y.,
RA Garcia-Morin M., Barredo-Valderrama E.;
RT "Periventricular nodular heterotopia and dystonia due to an ARFGEF2
RT mutation.";
RL Pediatr. Neurol. 51:461-464(2014).
RN [31]
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., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [32]
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., Gilissen C.,
RA del Rosario M., Hoischen A., Scheffer H., de Vries B.B., Brunner H.G.,
RA 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 and to
CC a lower extent on ARF5 and ARF6. Promotes the activation of
CC ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the
CC regulation of Golgi vesicular transport. Required for the integrity of
CC the endosomal compartment. Involved in trafficking from the trans-Golgi
CC network (TGN) to endosomes and is required for membrane association of
CC the AP-1 complex and GGA1. Seems to be involved in recycling of the
CC transferrin receptor from recycling endosomes to the plasma membrane.
CC Probably is involved in the exit of GABA(A) receptors from the
CC endoplasmic reticulum. Involved in constitutive release of tumor
CC necrosis factor receptor 1 via exosome-like vesicles; the function
CC seems to involve PKA and specifically PRKAR2B. Proposed to act as A
CC kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf
CC and PKA pathways. {ECO:0000269|PubMed:12051703,
CC ECO:0000269|PubMed:12571360, ECO:0000269|PubMed:15385626,
CC ECO:0000269|PubMed:16477018, ECO:0000269|PubMed:17276987,
CC ECO:0000269|PubMed:18625701, ECO:0000269|PubMed:20360857}.
CC -!- ACTIVITY REGULATION: Inhibited by brefeldin A.
CC -!- SUBUNIT: Homodimer (Probable). Interacts with ARFGEF1/BIG1; both
CC proteins are probably part of the same or very similar macromolecular
CC complexes. Interacts with PRKAR1A, PRKAR2A, PRKAR1B, PRKAR2B, PPP1CC,
CC PDE3A, TNFRSF1A, MYCBP and EXOC7. Interacts with GABRB1, GABRB2 and
CC GABRB3 (By similarity). {ECO:0000250, ECO:0000305}.
CC -!- INTERACTION:
CC Q9Y6D5; Q9Y6D6: ARFGEF1; NbExp=12; IntAct=EBI-2837511, EBI-1044254;
CC Q9Y6D5; Q9UPT5-1: EXOC7; NbExp=4; IntAct=EBI-2837511, EBI-6251402;
CC Q9Y6D5; Q99417: MYCBP; NbExp=5; IntAct=EBI-2837511, EBI-716185;
CC Q9Y6D5; Q14432: PDE3A; NbExp=5; IntAct=EBI-2837511, EBI-7192066;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane. Golgi apparatus. Cytoplasm,
CC perinuclear region. Golgi apparatus, trans-Golgi network {ECO:0000250}.
CC Endosome {ECO:0000250}. Cytoplasm, cytoskeleton, microtubule organizing
CC center, centrosome. Cell projection, dendrite {ECO:0000250}.
CC Cytoplasmic vesicle {ECO:0000250}. Synapse {ECO:0000250}. Cytoplasm,
CC cytoskeleton {ECO:0000250}. Note=Translocates from cytoplasm to
CC membranes upon cAMP treatment. Localized in recycling endosomes.
CC -!- TISSUE SPECIFICITY: Expressed in placenta, lung, heart, brain, kidney
CC and pancreas.
CC -!- PTM: In vitro phosphorylated by PKA reducing its GEF activity and
CC dephosphorylated by phosphatase PP1. {ECO:0000269|PubMed:17360629}.
CC -!- DISEASE: Periventricular nodular heterotopia 2 (PVNH2) [MIM:608097]: A
CC developmental disorder characterized by the presence of periventricular
CC nodules of cerebral gray matter, resulting from a failure of neurons to
CC migrate normally from the lateral ventricular proliferative zone, where
CC they are formed, to the cerebral cortex. PVNH2 is an autosomal
CC recessive form characterized by microcephaly (small brain), severe
CC developmental delay and recurrent infections. No anomalies extrinsic to
CC the central nervous system, such as dysmorphic features or grossly
CC abnormal endocrine or other conditions, are associated with PVNH2.
CC {ECO:0000269|PubMed:14647276, ECO:0000269|PubMed:23812912,
CC ECO:0000269|PubMed:25160555}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
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DR EMBL; AF084521; AAD38428.1; -; mRNA.
DR EMBL; AL049537; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL121903; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS13411.1; -.
DR RefSeq; NP_006411.2; NM_006420.2.
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 AlphaFoldDB; Q9Y6D5; -.
DR SMR; Q9Y6D5; -.
DR BioGRID; 115815; 130.
DR DIP; DIP-48794N; -.
DR IntAct; Q9Y6D5; 34.
DR MINT; Q9Y6D5; -.
DR STRING; 9606.ENSP00000360985; -.
DR ChEMBL; CHEMBL4105732; -.
DR iPTMnet; Q9Y6D5; -.
DR PhosphoSitePlus; Q9Y6D5; -.
DR BioMuta; ARFGEF2; -.
DR DMDM; 146329988; -.
DR EPD; Q9Y6D5; -.
DR jPOST; Q9Y6D5; -.
DR MassIVE; Q9Y6D5; -.
DR MaxQB; Q9Y6D5; -.
DR PaxDb; Q9Y6D5; -.
DR PeptideAtlas; Q9Y6D5; -.
DR PRIDE; Q9Y6D5; -.
DR ProteomicsDB; 86654; -.
DR Antibodypedia; 13512; 157 antibodies from 24 providers.
DR DNASU; 10564; -.
DR Ensembl; ENST00000371917.5; ENSP00000360985.4; ENSG00000124198.10.
DR GeneID; 10564; -.
DR KEGG; hsa:10564; -.
DR MANE-Select; ENST00000371917.5; ENSP00000360985.4; NM_006420.3; NP_006411.2.
DR UCSC; uc002xtx.5; human.
DR CTD; 10564; -.
DR DisGeNET; 10564; -.
DR GeneCards; ARFGEF2; -.
DR HGNC; HGNC:15853; ARFGEF2.
DR HPA; ENSG00000124198; Tissue enhanced (parathyroid).
DR MalaCards; ARFGEF2; -.
DR MIM; 605371; gene.
DR MIM; 608097; phenotype.
DR neXtProt; NX_Q9Y6D5; -.
DR OpenTargets; ENSG00000124198; -.
DR Orphanet; 98892; Periventricular nodular heterotopia.
DR PharmGKB; PA24945; -.
DR VEuPathDB; HostDB:ENSG00000124198; -.
DR eggNOG; KOG0929; Eukaryota.
DR GeneTree; ENSGT00940000158950; -.
DR HOGENOM; CLU_000691_1_2_1; -.
DR InParanoid; Q9Y6D5; -.
DR OMA; DLYITFF; -.
DR OrthoDB; 815698at2759; -.
DR PhylomeDB; Q9Y6D5; -.
DR TreeFam; TF300714; -.
DR PathwayCommons; Q9Y6D5; -.
DR Reactome; R-HSA-390471; Association of TriC/CCT with target proteins during biosynthesis.
DR SignaLink; Q9Y6D5; -.
DR BioGRID-ORCS; 10564; 10 hits in 1079 CRISPR screens.
DR ChiTaRS; ARFGEF2; human.
DR GeneWiki; ARFGEF2; -.
DR GenomeRNAi; 10564; -.
DR Pharos; Q9Y6D5; Tbio.
DR PRO; PR:Q9Y6D5; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; Q9Y6D5; protein.
DR Bgee; ENSG00000124198; Expressed in cartilage tissue and 208 other tissues.
DR Genevisible; Q9Y6D5; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0032279; C:asymmetric synapse; ISS:UniProtKB.
DR GO; GO:0005879; C:axonemal microtubule; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016020; C:membrane; IDA:MGI.
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:0050811; F:GABA receptor binding; ISS:UniProtKB.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0017022; F:myosin binding; IEA:Ensembl.
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 CDD; cd00171; Sec7; 1.
DR Gene3D; 1.10.1000.11; -; 1.
DR Gene3D; 1.25.10.10; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR032629; DCB_dom.
DR InterPro; IPR015403; Sec7_C.
DR InterPro; IPR023394; Sec7_C_sf.
DR InterPro; IPR000904; Sec7_dom.
DR InterPro; IPR035999; Sec7_dom_sf.
DR InterPro; IPR032691; Sec7_N.
DR Pfam; PF16213; DCB; 1.
DR Pfam; PF09324; DUF1981; 1.
DR Pfam; PF01369; Sec7; 1.
DR Pfam; PF12783; Sec7_N; 1.
DR SMART; SM00222; Sec7; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR SUPFAM; SSF48425; SSF48425; 1.
DR PROSITE; PS50190; SEC7; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell projection; Cytoplasm; Cytoplasmic vesicle;
KW Cytoskeleton; Disease variant; Endosome; Golgi apparatus;
KW Guanine-nucleotide releasing factor; Membrane; Phosphoprotein;
KW Protein transport; Reference proteome; Synapse; Transport.
FT CHAIN 1..1785
FT /note="Brefeldin A-inhibited guanine nucleotide-exchange
FT protein 2"
FT /id="PRO_0000120208"
FT DOMAIN 654..785
FT /note="SEC7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00189"
FT REGION 2..224
FT /note="DCB; DCB:DCB domain and DCB:HUS domain interaction"
FT REGION 232..285
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 508..528
FT /note="HUS; DCB:HUS domain interaction"
FT REGION 1514..1535
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 233..247
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 248..269
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 214
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 218
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:24275569"
FT MOD_RES 227
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 244
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 277
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 348
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7TSU1"
FT MOD_RES 349
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 614
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 616
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:A2A5R2"
FT MOD_RES 617
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:A2A5R2"
FT MOD_RES 626
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:A2A5R2"
FT MOD_RES 700
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 1511
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1513
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7TSU1"
FT MOD_RES 1514
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7TSU1"
FT MOD_RES 1525
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT MOD_RES 1528
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1534
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7TSU1"
FT MOD_RES 1782
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT VARIANT 209
FT /note="E -> K (in PVNH2; unknown pathological significance;
FT dbSNP:rs28937880)"
FT /evidence="ECO:0000269|PubMed:14647276"
FT /id="VAR_037438"
FT VARIANT 527
FT /note="A -> V (in dbSNP:rs6063343)"
FT /id="VAR_028750"
FT VARIANT 794
FT /note="K -> E (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036156"
FT VARIANT 802
FT /note="R -> Q (in dbSNP:rs748482139)"
FT /evidence="ECO:0000269|PubMed:23033978"
FT /id="VAR_069404"
FT MUTAGEN 289
FT /note="V->W: Abolishes interaction with PRKAR2B and impairs
FT TNFRSF1A release."
FT /evidence="ECO:0000269|PubMed:18625701"
FT MUTAGEN 534
FT /note="V->W: Abolishes interaction with PRKAR2B and impairs
FT TNFRSF1A release."
FT /evidence="ECO:0000269|PubMed:18625701"
FT MUTAGEN 738
FT /note="E->K: Disturbs membrane organization at the TGN,
FT impairs association of the AP-1 complex and GGA1 with the
FT TGN membranes."
FT /evidence="ECO:0000269|PubMed:12051703,
FT ECO:0000269|PubMed:15385626"
FT CONFLICT 207
FT /note="E -> R (in Ref. 1; AAD38428)"
FT /evidence="ECO:0000305"
FT CONFLICT 962
FT /note="E -> K (in Ref. 1; AAD38428)"
FT /evidence="ECO:0000305"
FT CONFLICT 1049
FT /note="D -> N (in Ref. 1; AAD38428)"
FT /evidence="ECO:0000305"
FT CONFLICT 1763
FT /note="G -> S (in Ref. 1; AAD38428)"
FT /evidence="ECO:0000305"
FT HELIX 641..643
FT /evidence="ECO:0007829|PDB:3SWV"
FT TURN 644..648
FT /evidence="ECO:0007829|PDB:3SWV"
FT HELIX 649..654
FT /evidence="ECO:0007829|PDB:3L8N"
FT HELIX 658..667
FT /evidence="ECO:0007829|PDB:3L8N"
FT TURN 674..678
FT /evidence="ECO:0007829|PDB:3L8N"
FT HELIX 679..682
FT /evidence="ECO:0007829|PDB:3L8N"
FT HELIX 690..694
FT /evidence="ECO:0007829|PDB:3L8N"
FT TURN 695..698
FT /evidence="ECO:0007829|PDB:3L8N"
FT TURN 702..705
FT /evidence="ECO:0007829|PDB:3L8N"
FT HELIX 706..712
FT /evidence="ECO:0007829|PDB:3L8N"
FT HELIX 723..729
FT /evidence="ECO:0007829|PDB:3L8N"
FT HELIX 739..753
FT /evidence="ECO:0007829|PDB:3L8N"
FT HELIX 766..777
FT /evidence="ECO:0007829|PDB:3L8N"
FT TURN 778..782
FT /evidence="ECO:0007829|PDB:3L8N"
FT TURN 796..798
FT /evidence="ECO:0007829|PDB:3L8N"
FT STRAND 799..801
FT /evidence="ECO:0007829|PDB:3L8N"
FT STRAND 804..808
FT /evidence="ECO:0007829|PDB:3SWV"
FT HELIX 812..822
FT /evidence="ECO:0007829|PDB:3L8N"
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
