Reviewed, UniProtKB/Swiss-Prot Q99490 (AGAP2_HUMAN)

Names and origin

Protein names

Recommended name:
    Arf-GAP, GTPase, ANK repeat and PH domain-containing protein 2
      Short name=AGAP-2
Alternative name(s):
    Centaurin-gamma-1
    Phosphatidylinositol-3-kinase enhancer
      Short name=PIKE
    GTP-binding and GTPase-activating protein 2
      Short name=GGAP2

Gene names

Name:	AGAP2
Synonyms:	CENTG1, KIAA0167

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1192 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. Ref.3 Ref.8 Ref.9 Ref.10
Enzyme regulation	GAP activity is stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and, to a lesser extent, by phosphatidylinositol 3,4,5-trisphosphate (PIP3). Phosphatidic acid potentiates PIP2 stimulation.
Subunit structure	Isoform 1 interacts with EPB41L1, PLCG1, NF2, HOMER1 and HOMER2 By similarity. Isoform 2 interacts with activated AKT1 in the presence of guanine nucleotides, and with the AP-1 complex.
Subcellular location	Isoform 1: Cytoplasm. Nucleus. Ref.3 Ref.8 Ref.13 Isoform 2: Cytoplasm. Ref.3 Ref.8 Ref.13
Tissue specificity	Isoform 1 is brain-specific. Isoform 2 is ubiquitously expressed, with highest levels in brain and heart. Ref.3 Ref.8 Ref.9 Ref.10 Ref.11
Domain	G domain binds GTP and has GTPase activity. Arf-GAP domain interacts with G domain and may regulate its GTPase activity. Although both PH domains of isoforms 1 and 2 bind phospholipids, they differently regulate subcellular location. PH domain of isoform 1 directs the protein to the nucleus, but PH domain of isoform 2 directs it to the cytosol. PH domain of isoform 2 is required for binding to AP-1.
Miscellaneous	Isoform 2 seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion.
Sequence similarities	Belongs to the centaurin gamma-like family. Contains 2 ANK repeats. Contains 1 Arf-GAP domain. Contains 1 PH domain.

Ontologies

Keywords
Biological process	Protein transport Transport
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Domain	ANK repeat Repeat Zinc-finger
Ligand	GTP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	GTPase activation Oncogene
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	protein transport Inferred from electronic annotation. Source: UniProtKB-KW regulation of ARF GTPase activity Inferred from electronic annotation. Source: InterPro small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	ARF GTPase activator activity Inferred from electronic annotation. Source: InterPro GTP binding Inferred from electronic annotation. Source: UniProtKB-KW GTPase activity Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q99490-1)

Also known as: PIKE-L;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q99490-2)

Also known as: PIKE-A;

The sequence of this isoform differs from the canonical sequence as follows:
     1-336: Missing.
     337-390: ASTRDRKMLK...LGAELRASPK → MHAQRQFVVA...IQASLDSIRE
     853-872: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1192

1192

Arf-GAP, GTPase, ANK repeat and PH domain-containing protein 2

PRO_0000074217

Regions

Domain

676 – 910

235

PH

Domain

931 – 1051

121

Arf-GAP

Repeat

1090 – 1119

30

ANK 1

Repeat

1123 – 1152

30

ANK 2

Nucleotide binding

413 – 420

8

GTP Potential

Nucleotide binding

457 – 461

5

GTP Potential

Nucleotide binding

515 – 518

4

GTP Potential

Zinc finger

946 – 969

24

C4-type

Region

1 – 23

23

Interaction with EPB41L1 By similarity

Region

180 – 225

46

Interactions with HOMER1 and NF2 By similarity

Region

267 – 390

124

Interaction with PLCG1 By similarity

Region

405 – 572

168

G domain

Amino acid modifications

Modified residue

149

1

Phosphoserine By similarity

Modified residue

267

1

Phosphoserine By similarity

Modified residue

638

1

Phosphoserine By similarity

Modified residue

808

1

Phosphoserine By similarity

Modified residue

865

1

Phosphoserine By similarity

Modified residue

927

1

Phosphoserine By similarity

Natural variations

Alternative sequence

1 – 336

336

Missing in isoform 2.

VSP_018531

Alternative sequence

337 – 390

54

ASTRD…RASPK → MHAQRQFVVAAVRAEVRRHE VAKQALNRLRKLAERVDDPE LQDSIQASLDSIRE in isoform 2.

VSP_018532

Alternative sequence

853 – 872

20

Missing in isoform 2.

VSP_018533

Natural variant

339

1

T → A in a breast cancer sample; somatic mutation. Ref.14

VAR_036183

Natural variant

455

1

V → A in a glioblastoma cell line. Ref.13

VAR_026438

Natural variant

507

1

G → S: dbSNP rs2301553.

VAR_022046

Natural variant

518

1

R → G in a sarcoma cell line. Ref.13

VAR_026439

Natural variant

568

1

T → I in a neuroblastoma cell line. Ref.13

VAR_026440

Natural variant

651

1

A → V in a glioblastoma cell line. Ref.13

VAR_026441

Natural variant

767

1

E → V in a glioblastoma cell line. Ref.13

VAR_026442

Natural variant

816

1

D → Y in a breast cancer sample; somatic mutation. Ref.14

VAR_036184

Natural variant

939

1

N → D in a glioblastoma cell line. Ref.13

VAR_026443

Natural variant

947

1

V → M in a sarcoma cell line. Ref.13

VAR_026444

Natural variant

1022

1

S → P in a glioblastoma cell line. Ref.13

VAR_026445

Natural variant

1124

1

G → V: dbSNP rs238521.

VAR_055532

Experimental info

Sequence conflict

1137

1

Q → H in AAC39522. Ref.1

Sequence conflict

1147

1

G → A in AAC39522. Ref.1

Secondary structure

1

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1192

Helix Strand Turn

Details...

Beta strand

406 – 412

7

Turn

415 – 418

4

Helix

419 – 428

10

Beta strand

440 – 448

9

Beta strand

451 – 459

9

Helix

466 – 471

6

Beta strand

473 – 480

8

Helix

484 – 500

17

Beta strand

509 – 515

7

Beta strand

521 – 523

3

Helix

529 – 537

9

Beta strand

542 – 548

7

Turn

549 – 552

4

Helix

555 – 575

21

Beta strand

677 – 686

10

Beta strand

695 – 703

9

Turn

704 – 706

3

Beta strand

707 – 713

7

Helix

714 – 719

6

Beta strand

724 – 730

7

Beta strand

732 – 734

3

Beta strand

765 – 768

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (PIKE-L) [UniParc]. Last modified May 16, 2006. Version 2. Checksum: 8DA53707C0127984	FASTA	1,192	124,674
	10 20 30 40 50 60 MSRGAGALQR RTTTYLISLT LVKLESVPPP PPSPSAAAVG APGARGSEPR DPGSPRGAEE 70 80 90 100 110 120 PGKKRHERLF HRQDALWIST SSAGAGGAEP PALSPAPASP ARPVSPAPGR RLSLWAAPPG 130 140 150 160 170 180 PPLSGGLSPD SKPGGAPSSS RRPLLSSPSW GGPEPEGRTG GGVPGSSSPH PGTGSRRLKV 190 200 210 220 230 240 APPPPAPKPC KTVTTSGAKA GGGKGAGSRL SWPESEGKPR VKGSKSSAGT GASVSAAATA 250 260 270 280 290 300 AAAGGGGSTA STSGGVGAGA GARGKLSPRK GKSKTLDNSD LHPGPPAGSP PPLTLPPTPS 310 320 330 340 350 360 PATAVTAASA QPPGPAPPIT LEPPAPGLKR GREGGRASTR DRKMLKFISG IFTKSTGGPP 370 380 390 400 410 420 GSGPLPGPPS LSSGSGSREL LGAELRASPK AVINSQEWTL SRSIPELRLG VLGDARSGKS 430 440 450 460 470 480 SLIHRFLTGS YQVLEKTESE QYKKEMLVDG QTHLVLIREE AGAPDAKFSG WADAVIFVFS 490 500 510 520 530 540 LEDENSFQAV SRLHGQLSSL RGEGRGGLAL ALVGTQDRIS ASSPRVVGDA RARALCADMK 550 560 570 580 590 600 RCSYYETCAT YGLNVDRVFQ EVAQKVVTLR KQQQLLAACK SLPSSPSHSA ASTPVAGQAS 610 620 630 640 650 660 NGGHTSDYSS SLPSSPNVGH RELRAEAAAV AGLSTPGSLH RAAKRRTSLF ANRRGSDSEK 670 680 690 700 710 720 RSLDSRGETT GSGRAIPIKQ SFLLKRSGNS LNKEWKKKYV TLSSNGFLLY HPSINDYIHS 730 740 750 760 770 780 THGKEMDLLR TTVKVPGKRP PRAISAFGPS ASINGLVKDM STVQMGEGLE ATTPMPSPSP 790 800 810 820 830 840 SPSSLQPPPD QTSKHLLKPD RNLARALSTD CTPSGDLSPL SREPPPSPMV KKQRRKKLTT 850 860 870 880 890 900 PSKTEGSAGQ AEAKRKMWKL KSFGSLRNIY KAEENFEFLI VSSTGQTWHF EAASFEERDA 910 920 930 940 950 960 WVQAIESQIL ASLQCCESSK VKLRTDSQSE AVAIQAIRNA KGNSICVDCG APNPTWASLN 970 980 990 1000 1010 1020 LGALICIECS GIHRNLGTHL SRVRSLDLDD WPRELTLVLT AIGNDTANRV WESDTRGRAK 1030 1040 1050 1060 1070 1080 PSRDSSREER ESWIRAKYEQ LLFLAPLSTS EEPLGRQLWA AVQAQDVATV LLLLAHARHG 1090 1100 1110 1120 1130 1140 PLDTSVEDPQ LRSPLHLAAE LAHVVITQLL LWYGADVAAR DAQGRTALFY ARQAGSQLCA 1150 1160 1170 1180 1190 DILLQHGCPG EGGSAATTPS AATTPSITAT PSPRRRSSAA SVGRADAPVA LV
	Isoform 2 (PIKE-A). Checksum: B8E42631BC06D5DC	FASTA	836	90,537
	10 20 30 40 50 60 MHAQRQFVVA AVRAEVRRHE VAKQALNRLR KLAERVDDPE LQDSIQASLD SIREAVINSQ 70 80 90 100 110 120 EWTLSRSIPE LRLGVLGDAR SGKSSLIHRF LTGSYQVLEK TESEQYKKEM LVDGQTHLVL 130 140 150 160 170 180 IREEAGAPDA KFSGWADAVI FVFSLEDENS FQAVSRLHGQ LSSLRGEGRG GLALALVGTQ 190 200 210 220 230 240 DRISASSPRV VGDARARALC ADMKRCSYYE TCATYGLNVD RVFQEVAQKV VTLRKQQQLL 250 260 270 280 290 300 AACKSLPSSP SHSAASTPVA GQASNGGHTS DYSSSLPSSP NVGHRELRAE AAAVAGLSTP 310 320 330 340 350 360 GSLHRAAKRR TSLFANRRGS DSEKRSLDSR GETTGSGRAI PIKQSFLLKR SGNSLNKEWK 370 380 390 400 410 420 KKYVTLSSNG FLLYHPSIND YIHSTHGKEM DLLRTTVKVP GKRPPRAISA FGPSASINGL 430 440 450 460 470 480 VKDMSTVQMG EGLEATTPMP SPSPSPSSLQ PPPDQTSKHL LKPDRNLARA LSTDCTPSGD 490 500 510 520 530 540 LSPLSREPPP SPMVKKQRRK KLTTPSKTEG SAGQAEEENF EFLIVSSTGQ TWHFEAASFE 550 560 570 580 590 600 ERDAWVQAIE SQILASLQCC ESSKVKLRTD SQSEAVAIQA IRNAKGNSIC VDCGAPNPTW 610 620 630 640 650 660 ASLNLGALIC IECSGIHRNL GTHLSRVRSL DLDDWPRELT LVLTAIGNDT ANRVWESDTR 670 680 690 700 710 720 GRAKPSRDSS REERESWIRA KYEQLLFLAP LSTSEEPLGR QLWAAVQAQD VATVLLLLAH 730 740 750 760 770 780 ARHGPLDTSV EDPQLRSPLH LAAELAHVVI TQLLLWYGAD VAARDAQGRT ALFYARQAGS 790 800 810 820 830 QLCADILLQH GCPGEGGSAA TTPSAATTPS ITATPSPRRR SSAASVGRAD APVALV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Transcript mapping in a 46-kb sequenced region at the core of 12q13.3 amplification in human cancers." Elkahloun A.G., Krizman D.B., Wang Z., Hofmann T.A., Roe B.A., Meltzer P.S. Genomics 42:295-301(1997) [PubMed: 9192850] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING (ISOFORM 2), VARIANT VAL-1124.
[2]	Roe B. Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO 389; 768-769; 1124; 1137 AND 1147 (ISOFORM 2).
[3]	"GGAPs, a new family of bifunctional GTP-binding and GTPase-activating proteins." Xia C., Ma W., Stafford L.J., Liu C., Gong L., Martin J.F., Liu M. Mol. Cell. Biol. 23:2476-2488(2003) [PubMed: 12640130] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, SUBCELLULAR LOCATION, FUNCTION. Tissue: Heart.
[4]	"PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis." Rong R., Ahn J.-Y., Huang H., Nagata E., Kalman D., Kapp J.A., Tu J., Worley P.F., Snyder S.H., Ye K. Nat. Neurosci. 6:1153-1161(2003) [PubMed: 14528310] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]	"Kiaa0167 as a member (centaurin gamma1) of centaurin ArfGAP family." Hong W. Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[6]	"Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1." Nagase T., Seki N., Ishikawa K., Tanaka A., Nomura N. DNA Res. 3:17-24(1996) [PubMed: 8724849] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Bone marrow.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Blood.
[8]	"PIKE (phosphatidylinositol 3-kinase enhancer)-A GTPase stimulates Akt activity and mediates cellular invasion." Ahn J.-Y., Rong R., Kroll T.G., Van Meir E.G., Snyder S.H., Ye K. J. Biol. Chem. 279:16441-16451(2004) [PubMed: 14761976] [Abstract] Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION, INTERACTION WITH AKT1, FUNCTION.
[9]	"PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt." Ahn J.-Y., Hu Y., Kroll T.G., Allard P., Ye K. Proc. Natl. Acad. Sci. U.S.A. 101:6993-6998(2004) [PubMed: 15118108] [Abstract] Cited for: TISSUE SPECIFICITY, INTERACTION WITH AKT1, FUNCTION.
[10]	"The Arf GAPs AGAP1 and AGAP2 distinguish between the adaptor protein complexes AP-1 and AP-3." Nie Z., Fei J., Premont R.T., Randazzo P.A. J. Cell Sci. 118:3555-3566(2005) [PubMed: 16079295] [Abstract] Cited for: TISSUE SPECIFICITY, INTERACTION WITH THE AP-1 COMPLEX, FUNCTION.
[11]	"Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas." Knobbe C.B., Trampe-Kieslich A., Reifenberger G. Neuropathol. Appl. Neurobiol. 31:486-490(2005) [PubMed: 16150119] [Abstract] Cited for: TISSUE SPECIFICITY.
[12]	"Crystal structure of centaurin gamma 1." Yang X., Elkins J.M., Soundararajan M., Doyle D.A. Submitted (MAR-2005) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF N-TERMINUS (ISOFORM 2).
[13]	"Phosphoinositol lipids bind to phosphatidylinositol 3 (PI3)-kinase enhancer GTPase and mediate its stimulatory effect on PI3-kinase and Akt signalings." Hu Y., Liu Z., Ye K. Proc. Natl. Acad. Sci. U.S.A. 102:16853-16858(2005) [PubMed: 16263930] [Abstract] Cited for: VARIANTS ALA-455; GLY-518; ILE-568; VAL-651; VAL-767; ASP-939; MET-947 AND PRO-1022, SUBCELLULAR LOCATION.
[14]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ALA-339 AND TYR-816.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

U81031 Genomic DNA. Translation: AAC39522.2.
AF384128 mRNA. Translation: AAO39848.1.
AY128689 mRNA. Translation: AAM97540.1.
D79989 mRNA. Translation: BAA11484.2. Different initiation.
AF413077 mRNA. Translation: AAL04171.1.
BC028020 mRNA. Translation: AAH28020.1.

IPI

IPI00015401.
IPI00217393.

RefSeq

NP_001116244.1.
NP_055585.1.

UniGene

Hs.302435

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2BMJ	X-ray	2.10	A	402-577	[»]
2IWR	X-ray	1.50	A	402-577	[»]
2RLO	NMR	-	A	674-914	[»]

ModBase

Search...

PTM databases

PhosphoSite

Q99490.

Proteomic databases

PRIDE

Q99490.

Genome annotation databases

Ensembl

ENSG00000135439. Homo sapiens. [Contig view]

GeneID

116986.

KEGG

hsa:116986.

Organism-specific databases

GeneCards

GC12M056406.

H-InvDB

HIX0010751.
HIX0036788.

HGNC

HGNC:16921. AGAP2.

MIM

605476. gene.

PharmGKB

PA26411.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q99490.

HOVERGEN

Q99490.

Enzyme and pathway databases

Pathway_Interaction_DB

pi3kplctrkpathway. Trk receptor signaling mediated by PI3K and PLC-gamma.

Gene expression databases

ArrayExpress

Q99490.

Bgee

Q99490.

CleanEx

HS_AGAP2.

GermOnline

ENSG00000135439. Homo sapiens.

Family and domain databases

InterPro

IPR002110. ANK.
IPR001164. ArfGAP.
IPR013684. Miro-like.
IPR001849. Pleckstrin_homology.
[Graphical view]

Gene3D

G3DSA:1.25.40.20. ANK. 1 hit.

Pfam

PF00023. Ank. 2 hits.
PF01412. ArfGap. 1 hit.
PF08477. Miro. 1 hit.
PF00169. PH. 1 hit.
[Graphical view]

PRINTS

PR00405. REVINTRACTNG.

SMART

SM00248. ANK. 2 hits.
SM00105. ArfGap. 1 hit.
SM00233. PH. 1 hit.
[Graphical view]

PROSITE

PS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. 1 hit.
PS50115. ARFGAP. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS51419. RAB. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

80070.

SOURCE

Search...

Entry information

Entry name

AGAP2_HUMAN

Accession

Primary (citable) accession number: Q99490
Secondary accession number(s): O00578, Q548E0, Q8IWU3

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	May 16, 2006
Last modified:	June 16, 2009
This is version 106 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)