AGAP2_RAT
ID AGAP2_RAT Reviewed; 1186 AA.
AC Q8CGU4; Q9JHW8;
DT 16-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2;
DE Short=AGAP-2;
DE AltName: Full=Centaurin-gamma-1;
DE Short=Cnt-g1;
DE AltName: Full=Phosphatidylinositol 3-kinase enhancer;
DE Short=PIKE;
GN Name=Agap2; Synonyms=Centg1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, SUBCELLULAR LOCATION,
RP INTERACTION WITH HOMER1 AND HOMER2, AND MUTAGENESIS OF PRO-187.
RC STRAIN=Brown Norway; TISSUE=Brain;
RX PubMed=14528310; DOI=10.1038/nn1134;
RA Rong R., Ahn J.-Y., Huang H., Nagata E., Kalman D., Kapp J.A., Tu J.,
RA Worley P.F., Snyder S.H., Ye K.;
RT "PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing
RT neuronal apoptosis.";
RL Nat. Neurosci. 6:1153-1161(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-754, GTP-BINDING, TISSUE SPECIFICITY,
RP INTERACTION WITH EPB41L1, SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS
RP OF SER-414.
RX PubMed=11136977; DOI=10.1016/s0092-8674(00)00195-1;
RA Ye K., Hurt K.J., Wu F.Y., Fang M., Luo H.R., Hong J.J., Blackshaw S.,
RA Ferris C.D., Snyder S.H.;
RT "PIKE: a nuclear GTPase that enhances PI3kinase activity and is regulated
RT by protein 4.1N.";
RL Cell 103:919-930(2000).
RN [3]
RP FUNCTION, AND INTERACTION WITH PLCG1.
RX PubMed=11823862; DOI=10.1038/415541a;
RA Ye K., Aghdasi B., Luo H.R., Moriarity J.L., Wu F.Y., Hong J.J., Hurt K.J.,
RA Bae S.S., Suh P.-G., Snyder S.H.;
RT "Phospholipase C gamma 1 is a physiological guanine nucleotide exchange
RT factor for the nuclear GTPase PIKE.";
RL Nature 415:541-544(2002).
RN [4]
RP FUNCTION.
RX PubMed=15385964; DOI=10.1038/sj.emboj.7600392;
RA Ahn J.-Y., Rong R., Liu X., Ye K.;
RT "PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of
RT NGF in the nucleus.";
RL EMBO J. 23:3995-4006(2004).
RN [5]
RP SUBCELLULAR LOCATION, INTERACTION WITH NF2, AND MUTAGENESIS OF PRO-187.
RX PubMed=15598747; DOI=10.1073/pnas.0405971102;
RA Rong R., Tang X., Gutmann D.H., Ye K.;
RT "Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits
RT phosphatidylinositol 3-kinase through binding to PIKE-L.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:18200-18205(2004).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-679 AND LYS-687.
RX PubMed=16263930; DOI=10.1073/pnas.0507365102;
RA Hu Y., Liu Z., Ye K.;
RT "Phosphoinositol lipids bind to phosphatidylinositol 3 (PI3)-kinase
RT enhancer GTPase and mediate its stimulatory effect on PI3-kinase and Akt
RT signalings.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:16853-16858(2005).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1172, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: GTPase-activating protein (GAP) for ARF1 and ARF5, which also
CC shows strong GTPase activity. Participates in the prevention of
CC neuronal apoptosis by enhancing PI3 kinase activity. Aids the coupling
CC of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase
CC by interacting with Homer scaffolding proteins, and also seems to
CC mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase.
CC {ECO:0000269|PubMed:11136977, ECO:0000269|PubMed:11823862,
CC ECO:0000269|PubMed:15385964, ECO:0000269|PubMed:16263930}.
CC -!- ACTIVITY REGULATION: GAP activity is stimulated by phosphatidylinositol
CC 4,5-bisphosphate (PIP2) and, to a lesser extent, by
CC phosphatidylinositol 3,4,5-trisphosphate (PIP3). Phosphatidic acid
CC potentiates PIP2 stimulation (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Interacts with EPB41L1, PLCG1, NF2, HOMER1 and HOMER2.
CC {ECO:0000269|PubMed:11136977, ECO:0000269|PubMed:11823862,
CC ECO:0000269|PubMed:14528310, ECO:0000269|PubMed:15598747}.
CC -!- INTERACTION:
CC Q8CGU4; Q63155: Dcc; NbExp=2; IntAct=EBI-4409108, EBI-1798965;
CC Q8CGU4; P19491: Gria2; NbExp=4; IntAct=EBI-4409108, EBI-77718;
CC Q8CGU4; P97879: Grip1; NbExp=4; IntAct=EBI-4409108, EBI-936113;
CC Q8CGU4; Q9Z214-1: Homer1; NbExp=4; IntAct=EBI-4409108, EBI-4410552;
CC Q8CGU4; O08722: Unc5b; NbExp=6; IntAct=EBI-4409108, EBI-4404185;
CC Q8CGU4; Q8IZJ1: UNC5B; Xeno; NbExp=9; IntAct=EBI-4409108, EBI-4409075;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: Present in cortex, hippocampus and olfactory bulb
CC but absent in cerebellum (at protein level).
CC {ECO:0000269|PubMed:11136977, ECO:0000269|PubMed:14528310}.
CC -!- DOMAIN: G domain binds GTP and has GTPase activity. {ECO:0000250}.
CC -!- DOMAIN: Arf-GAP domain interacts with G domain and may regulate its
CC GTPase activity. {ECO:0000250}.
CC -!- DOMAIN: PH domain binds phospholipids and is required for nuclear
CC targeting. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the centaurin gamma-like family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF97595.1; Type=Frameshift; Note=This sequence would represent a shorter strictly nuclear isoform named PIKE-S. It may be an artifactual frameshifted form whose existence in vivo is dubious.; Evidence={ECO:0000305};
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DR EMBL; AY128688; AAM97539.1; -; mRNA.
DR EMBL; AF280816; AAF97595.1; ALT_FRAME; mRNA.
DR RefSeq; NP_075415.2; NM_023026.2.
DR AlphaFoldDB; Q8CGU4; -.
DR SMR; Q8CGU4; -.
DR BioGRID; 249323; 5.
DR IntAct; Q8CGU4; 10.
DR MINT; Q8CGU4; -.
DR STRING; 10116.ENSRNOP00000029533; -.
DR iPTMnet; Q8CGU4; -.
DR PhosphoSitePlus; Q8CGU4; -.
DR PaxDb; Q8CGU4; -.
DR PRIDE; Q8CGU4; -.
DR Ensembl; ENSRNOT00000031230; ENSRNOP00000029533; ENSRNOG00000025584.
DR GeneID; 65218; -.
DR KEGG; rno:65218; -.
DR CTD; 116986; -.
DR RGD; 628844; Agap2.
DR eggNOG; KOG0705; Eukaryota.
DR GeneTree; ENSGT00940000158956; -.
DR HOGENOM; CLU_007326_3_0_1; -.
DR InParanoid; Q8CGU4; -.
DR OMA; EWTMSQP; -.
DR OrthoDB; 751525at2759; -.
DR PhylomeDB; Q8CGU4; -.
DR TreeFam; TF317762; -.
DR PRO; PR:Q8CGU4; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000025584; Expressed in frontal cortex and 18 other tissues.
DR ExpressionAtlas; Q8CGU4; baseline and differential.
DR Genevisible; Q8CGU4; RN.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005768; C:endosome; ISO:RGD.
DR GO; GO:0090543; C:Flemming body; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0005524; F:ATP binding; ISO:RGD.
DR GO; GO:0005525; F:GTP binding; ISO:RGD.
DR GO; GO:0005096; F:GTPase activator activity; ISO:RGD.
DR GO; GO:0003924; F:GTPase activity; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0035014; F:phosphatidylinositol 3-kinase regulator activity; ISO:RGD.
DR GO; GO:0030295; F:protein kinase activator activity; IDA:RGD.
DR GO; GO:0019901; F:protein kinase binding; IDA:RGD.
DR GO; GO:0030036; P:actin cytoskeleton organization; ISO:RGD.
DR GO; GO:0090630; P:activation of GTPase activity; IBA:GO_Central.
DR GO; GO:0016197; P:endosomal transport; ISO:RGD.
DR GO; GO:1904019; P:epithelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0060749; P:mammary gland alveolus development; ISO:RGD.
DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD.
DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IMP:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:UniProtKB.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISO:RGD.
DR GO; GO:0033601; P:positive regulation of mammary gland epithelial cell proliferation; ISO:RGD.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IMP:UniProtKB.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; ISO:RGD.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0007259; P:receptor signaling pathway via JAK-STAT; IEA:Ensembl.
DR Gene3D; 1.10.220.150; -; 1.
DR Gene3D; 1.25.40.20; -; 1.
DR Gene3D; 2.30.29.30; -; 2.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR InterPro; IPR037278; ARFGAP/RecO.
DR InterPro; IPR001164; ArfGAP_dom.
DR InterPro; IPR038508; ArfGAP_dom_sf.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR001806; Small_GTPase.
DR Pfam; PF12796; Ank_2; 1.
DR Pfam; PF01412; ArfGap; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00405; REVINTRACTNG.
DR SMART; SM00105; ArfGap; 1.
DR SMART; SM00233; PH; 1.
DR SUPFAM; SSF48403; SSF48403; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF57863; SSF57863; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 1.
DR PROSITE; PS50115; ARFGAP; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS51419; RAB; 1.
PE 1: Evidence at protein level;
KW ANK repeat; Cytoplasm; GTP-binding; GTPase activation; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW Zinc; Zinc-finger.
FT CHAIN 1..1186
FT /note="Arf-GAP with GTPase, ANK repeat and PH domain-
FT containing protein 2"
FT /id="PRO_0000235914"
FT DOMAIN 670..904
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 925..1045
FT /note="Arf-GAP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00288"
FT REPEAT 1084..1113
FT /note="ANK 1"
FT REPEAT 1117..1146
FT /note="ANK 2"
FT ZN_FING 940..963
FT /note="C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00288"
FT REGION 1..23
FT /note="Interaction with EPB41L1"
FT /evidence="ECO:0000269|PubMed:11136977"
FT REGION 24..371
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 180..225
FT /note="Interactions with HOMER1 and NF2"
FT REGION 262..384
FT /note="Interaction with PLCG1"
FT /evidence="ECO:0000269|PubMed:11823862"
FT REGION 399..566
FT /note="G domain"
FT /evidence="ECO:0000250"
FT REGION 576..613
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 628..666
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 759..784
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 800..844
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1145..1174
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 52..73
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 576..611
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 644..661
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 407..414
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000255"
FT BINDING 451..455
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000255"
FT BINDING 509..512
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000255"
FT MOD_RES 113
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 128
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 149
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 632
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99490"
FT MOD_RES 744
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 746
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 802
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 921
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 979
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3UHD9"
FT MOD_RES 1172
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MUTAGEN 187
FT /note="P->L: Abolishes interactions with HOMER1C and NF2."
FT /evidence="ECO:0000269|PubMed:14528310,
FT ECO:0000269|PubMed:15598747"
FT MUTAGEN 414
FT /note="S->N: Fails to activate PI3 kinase."
FT /evidence="ECO:0000269|PubMed:11136977"
FT MUTAGEN 679
FT /note="K->N: Abolishes phospholipid binding and nuclear
FT localization; when associated with N-687."
FT /evidence="ECO:0000269|PubMed:16263930"
FT MUTAGEN 687
FT /note="K->N: Abolishes phospholipid binding and nuclear
FT localization; when associated with N-679."
FT /evidence="ECO:0000269|PubMed:16263930"
SQ SEQUENCE 1186 AA; 124438 MW; B9C8E987D2989378 CRC64;
MSRGAGALQR RTTTYLISLT LVKLESVPPP PPSPSAAAVG APGARGSEPR DPGSPRGAEE
PGKKRHERLF HRQDALWIST SSAGAGGAEP PALSPAPASP ARPVSPAPGR RLSLWAAPPG
PPLSGGLSPD SKPGGAPSSS RRPLLSSPSW GGPEPEGRTG GGVPGSSSPH PGTGSRRLKV
APPPPAPKPF KTVTTSGAKA GGGKGAGSRL SWPESEGKPR VKGSKSTAGT GASAVAAGGG
GSAAVTTSGG VGAGAGARGK LSPRKGKSKT LDNSDLHPGP SAGSPPLTVP AIPVPATSVT
AASTQPLGPA PPITLEPPAP GLKRGREGGR ASTRDRKMLK FISGIFTKST GGPPGPGPLP
GPQGLSSSSG SRELLGAELR ASPKAVVNSQ EWTLSRSIPE LRLGVLGDVR SGKSSLIHRF
LTGSYQVLEK PESEQYKKEM LVDGQTHLVL IREEAGAPDA KFSGWADAVI FVFSLEDESS
FQAVSHLHGQ LISLRGEGRG GLALALVGTQ DRISASSPRV VGDARARALC TDMKRCSYYE
TCATYGLNVD RVFQEVAQKV VTLRKQQQLL AACKSLPSSP SHSAASTPVA GQASNGGHTS
DYSSSLPSSP NVGHRELRAE AAAVAGLSTP GSLHRAAKRR TSLFANRRGS DSEKRSLDSR
GETTGSGRAI PIKQSFLLKR SGNSLNKEWK KKYVTLSSNG FLLYHPSIND YIHSTHGKEM
DLLRTTVKVP GKRPPRAISA FGPSASINGL VKDMSTVQMG EGPEASTPMP SPSPSPSSLQ
LPTDQTSKHL LKPDRNLARA LSTDCTPSGD LSPLSREPPP SPMVKKQRRK KLSTPSKTEG
SAVQAEAKRK MWKLKSFGSL RNIYKAEENF EFLIVSSTGQ TWHFEAASFE ERDAWVQAIE
SQILASLQCC ESSKVKLRTD SQSEAVAIQA IRNAKGNSTC VDCGAPNPTW ASLNLGALIC
IECSGIHRNL GTHLSRVRSL DLDDWPRELT LVLTAIGNDT ANRVWESDTR GRAKPTRDSS
REERESWIRA KYEQLLFLAP LGTTEEPLGR QLWAAVEAQD VAAVLLLLAH ARHGPLDTSV
EDPQLRSPLH LAAELAHVVI TQLLLWYGAD VAARDAQGRT ALFYARQAGS QLCADILLQH
GCPGEGGSTA TTPSAATTPS ITATPSPRRR SSAASLGRVD TTIALV
