P23727 (P85A_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Phosphatidylinositol 3-kinase regulatory subunit alpha
Short name=PI3-kinase regulatory subunit alpha
Short name=PI3K regulatory subunit alpha
Short name=PtdIns-3-kinase regulatory subunit alpha

Alternative name(s):
Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha
Short name=PI3-kinase subunit p85-alpha
Short name=PtdIns-3-kinase regulatory subunit p85-alpha

Gene names

Name:

PIK3R1

Organism

Bos taurus (Bovine) [Reference proteome]

Taxonomic identifier

9913 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Bovinae › Bos

Protein attributes

Sequence length	724 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling By similarity.
Subunit structure	Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts with phosphorylated LAT, LAX1, TRAT1 and LIME1 upon TCR and/or BCR activation. Interacts with CBLB. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with SOCS7. Interacts with IRS1 and phosphorylated IRS4. Interacts with NISCH, RUFY3 and HCST. Interacts with LYN (via SH3 domain); this enhances enzyme activity. Interacts with AXL, FASLG, FER, FGR, HCK, KIT and BCR. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) By similarity. Interacts with PDGFRA (tyrosine phosphorylated). Interacts with ERBB4 (phosphorylated) By similarity. Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with PTK2/FAK1 By similarity. Interacts with PDGFRB (tyrosine phosphorylated). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Ref.3
Domain	The SH3 domain mediates the binding to CBLB By similarity.
Post-translational modification	Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation By similarity. Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated on tyrosine residues by TEK/TIE2. Phosphorylated by FGR. Phosphorylated by CSF1R. Phosphorylated by ERBB4. Dephosphorylated by PTPRJ By similarity. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear. Ref.8
Sequence similarities	Belongs to the PI3K p85 subunit family. Contains 1 Rho-GAP domain. Contains 2 SH2 domains. Contains 1 SH3 domain.

Ontologies

Keywords
Domain	Repeat SH2 domain SH3 domain
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	B cell differentiation Inferred from electronic annotation. Source: Compara NFAT protein import into nucleus Inferred from electronic annotation. Source: Compara cellular response to UV Inferred from electronic annotation. Source: Compara growth hormone receptor signaling pathway Inferred from electronic annotation. Source: Compara insulin receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB insulin-like growth factor receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of cell-matrix adhesion Inferred from electronic annotation. Source: Compara negative regulation of osteoclast differentiation Inferred from electronic annotation. Source: Compara phosphatidylinositol 3-kinase cascade Inferred from electronic annotation. Source: Compara phosphatidylinositol phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of apoptotic process Inferred from electronic annotation. Source: Compara positive regulation of cell migration Inferred from electronic annotation. Source: Compara positive regulation of establishment of protein localization to plasma membrane Inferred from mutant phenotype PubMed 8052599. Source: BHF-UCL positive regulation of glucose import Inferred from mutant phenotype PubMed 8052599. Source: BHF-UCL positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara protein phosphorylation Inferred from electronic annotation. Source: Compara
Cellular_component	1-phosphatidylinositol-4-phosphate 3-kinase, class IA complex Inferred from sequence or structural similarity. Source: UniProtKB membrane Inferred from electronic annotation. Source: Compara
Molecular_function	ErbB-3 class receptor binding Inferred from sequence or structural similarity. Source: UniProtKB insulin binding Inferred from electronic annotation. Source: Compara insulin receptor binding Inferred from sequence or structural similarity. Source: UniProtKB insulin receptor substrate binding Inferred from sequence or structural similarity. Source: UniProtKB insulin-like growth factor receptor binding Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylinositol 3-kinase regulator activity Inferred from sequence or structural similarity. Source: UniProtKB transmembrane receptor protein tyrosine kinase adaptor activity Inferred from direct assay PubMed 1322797. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Inpp5d	Q9ES52-1	2	EBI-520244,EBI-1452545	From a different organism.
KHDRBS1	Q07666	2	EBI-520244,EBI-1364	From a different organism.
PIK3CA	P32871	4	EBI-520244,EBI-1373130
RAB5A	P20339	5	EBI-520244,EBI-399437	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 724

724

Phosphatidylinositol 3-kinase regulatory subunit alpha

PRO_0000080757

Regions

Domain

3 – 79

77

SH3

Domain

113 – 301

189

Rho-GAP

Domain

333 – 428

96

SH2 1

Domain

624 – 718

95

SH2 2

Amino acid modifications

Modified residue

467

1

Phosphotyrosine By similarity

Modified residue

580

1

Phosphotyrosine By similarity

Modified residue

607

1

Phosphotyrosine By similarity

Modified residue

608

1

Phosphoserine Ref.8

Secondary structure

1

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724

Helix Strand Turn

Details...

Beta strand

7 – 10

4

Beta strand

29 – 31

3

Helix

37 – 39

3

Turn

50 – 52

3

Beta strand

55 – 60

6

Turn

61 – 64

4

Beta strand

65 – 78

14

Beta strand

331 – 333

3

Turn

341 – 344

4

Helix

345 – 349

5

Beta strand

354 – 357

4

Turn

362 – 364

3

Beta strand

370 – 378

9

Beta strand

386 – 388

3

Beta strand

393 – 395

3

Turn

403 – 405

3

Turn

408 – 411

4

Helix

413 – 415

3

Turn

418 – 420

3

Helix

617 – 619

3

Helix

621 – 623

3

Beta strand

625 – 628

4

Helix

631 – 638

8

Beta strand

645 – 650

6

Beta strand

652 – 655

4

Beta strand

657 – 663

7

Beta strand

666 – 675

10

Beta strand

678 – 682

5

Beta strand

688 – 690

3

Helix

691 – 700

10

Helix

703 – 705

3

Sequences

	Sequence		Length	Mass (Da)
	P23727 [UniParc]. Last modified November 1, 1991. Version 1. Checksum: EBDF6E754BBF7321	FASTA	724	83,497
	10 20 30 40 50 60 MSAEGYQYRA LYDYKKEREE DIDLHLGDIL TVNKGSLVAL GFSDGQEAKP EEIGWLNGYN 70 80 90 100 110 120 ETTGERGDFP GTYVEYIGRK KISPPTPKPR PPRPLPVAPG PSKTEADSEQ QASTLPDLAE 130 140 150 160 170 180 QFAPPDVAPP LLIKLVEAIE KKGLECSTLY RTQSSSNPAE LRQLLDCDTA SLDLEMFDVH 190 200 210 220 230 240 VLADAFKRYL LDLPNPVIPV AVSSELISLA PEVQSSEEYI QLLKKLIRSP SIPHQYWLTL 250 260 270 280 290 300 QYLLKHFFKL SQTSSKNLLN ARVLSELFSP LLFRFPAASS ENTEHLIKII EILISTEWNE 310 320 330 340 350 360 RQPAPALPPK PPKPTTVANN GMNNNMSLQD AEWYWGDISR EEVNEKLRDT ADGTFLVRDA 370 380 390 400 410 420 STKMHGDYTL TLRKGGNNKL IKIFHRDGKY GFSDPLTFNS VVELINHYRN ESLAQYNPKL 430 440 450 460 470 480 DVKLLYPVSK YQQDQVVKED NIEAVGKKLH EYNTQFQEKS REYDRLYEDY TRTSQEIQMK 490 500 510 520 530 540 RTAIEAFNET IKIFEEQCQT QERYSKEYIE KFKREGNETE IQRIMHNYEK LKSRISEIVD 550 560 570 580 590 600 SRRRLEEDLK KQAAEYREID KRMNSIKPDL IQLRKTRDQY LMWLTQKGVR QKKLNEWLGN 610 620 630 640 650 660 ENTEDQYSLV EDDEDLPHHD EKTWNVGSSN RNKAENLLRG KRDGTFLVRE SSKQGCYACS 670 680 690 700 710 720 VVVDGEVKHC VINKTATGYG FAEPYNLYSS LKELVLHYQH TSLVQHNDSL NVTLAYPVYA QQRR

References

[1]	"Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase." Otsu M., Hiles I.D., Goot I., Fry M.J., Ruiz-Larrea F., Panayotou G., Thompson A., Dhand R., Hsuan J., Totty N., Smith A.D., Morgan S.J., Courtneidge S.A., Parker P.J., Waterfield M.D. Cell 65:91-104(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Interaction of the p85 subunit of PI 3-kinase and its N-terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes." Panayotou G., Bax B., Gout I., Federwisch M., Wroblowski B., Dhand R., Fry M.J., Blundell T.L., Wollmer A., Waterfield M.D. EMBO J. 11:4261-4272(1992) [PubMed] [Europe PMC] [Abstract] Cited for: CIRCULAR DICHROISM ANALYSIS, FLUORESCENCE SPECTROSCOPY.
[3]	"GTPase-activating protein and phosphatidylinositol 3-kinase bind to distinct regions of the platelet-derived growth factor receptor beta subunit." Kazlauskas A., Kashishian A., Cooper J.A., Valius M. Mol. Cell. Biol. 12:2534-2544(1992) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PDGFRB.
[4]	"Solution structure and ligand-binding site of the SH3 domain of the p85 alpha subunit of phosphatidylinositol 3-kinase." Booker G.W., Gout I., Downing A.K., Driscoll P.C., Boyd J., Waterfield M.D., Campbell I.D. Cell 73:813-822(1993) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 1-84.
[5]	"Structure of an SH2 domain of the p85 alpha subunit of phosphatidylinositol-3-OH kinase." Booker G.W., Breeze A.L., Downing A.K., Panayotou G., Gout I., Waterfield M.D., Campbell I.D. Nature 358:684-687(1992) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 314-431.
[6]	"NMR analysis of interactions of a phosphatidylinositol 3'-kinase SH2 domain with phosphotyrosine peptides reveals interdependence of major binding sites." Guenther U.L., Liu Y., Sanford D., Bachovchin W.W., Schaffhausen B. Biochemistry 35:15570-15581(1996) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 321-434.
[7]	"Solution structure of the C-terminal SH2 domain of the p85 alpha regulatory subunit of phosphoinositide 3-kinase." Siegal G., Davis B., Kristensen S.M., Sankar A., Linacre J., Stein R.C., Panayotou G., Waterfield M.D., Driscoll P.C. J. Mol. Biol. 276:461-478(1998) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 614-724.
[8]	"Regulation of phosphoinositide 3-kinase by its intrinsic serine kinase activity in vivo." Foukas L.C., Beeton C.A., Jensen J., Phillips W.A., Shepherd P.R. Mol. Cell. Biol. 24:966-975(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-608.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M61745 mRNA. Translation: AAA79511.1.

IPI

IPI00709792.

PIR

A38749.

RefSeq

NP_777000.1. NM_174575.1.

UniGene

Bt.109755.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BFI	NMR	-	A	614-724	[»]
1BFJ	NMR	-	A	614-724	[»]
1OO3	NMR	-	A	321-431	[»]
1OO4	NMR	-	A	321-431	[»]
1PNJ	NMR	-	A	1-84	[»]
1QAD	X-ray	1.80	A	614-724	[»]
2PNA	NMR	-	A	328-431	[»]
2PNB	NMR	-	A	328-431	[»]
2PNI	NMR	-	A	1-84	[»]

ProteinModelPortal

P23727.

SMR

P23727. Positions 1-84, 115-309, 328-600, 614-724.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-34247N.

IntAct

P23727. 10 interactions.

MINT

MINT-139236.

STRING

9913.ENSBTAP00000014594.

Proteomic databases

PRIDE

P23727.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSBTAT00000014594; ENSBTAP00000014594; ENSBTAG00000010989.

GeneID

282307.

KEGG

bta:282307.

Organism-specific databases

CTD

5295.

Phylogenomic databases

eggNOG

NOG263689.

GeneTree

ENSGT00390000010431.

HOGENOM

HOG000008438.

HOVERGEN

HBG082100.

InParanoid

P23727.

KO

K02649.

OMA

RPEEIGW.

OrthoDB

EOG4GXFM8.

Family and domain databases

Gene3D

1.10.555.10. 1 hit.
3.30.505.10. 2 hits.

InterPro

IPR001720. PI3kinase_P85.
IPR008936. Rho_GTPase_activation_prot.
IPR000198. RhoGAP_dom.
IPR000980. SH2.
IPR011511. SH3_2.
IPR001452. SH3_domain.
[Graphical view]

PANTHER

PTHR10155. PTHR10155. 1 hit.

Pfam

PF00620. RhoGAP. 1 hit.
PF00017. SH2. 2 hits.
PF07653. SH3_2. 1 hit.
[Graphical view]

PRINTS

PR00678. PI3KINASEP85.
PR00401. SH2DOMAIN.

SMART

SM00324. RhoGAP. 1 hit.
SM00252. SH2. 2 hits.
SM00326. SH3. 1 hit.
[Graphical view]

SUPFAM

SSF48350. Rho_GAP. 1 hit.
SSF50044. SH3. 1 hit.

PROSITE

PS50238. RHOGAP. 1 hit.
PS50001. SH2. 2 hits.
PS50002. SH3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P23727.

NextBio

20806106.

Entry information

Entry name

P85A_BOVIN

Accession

Primary (citable) accession number: P23727

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1991
Last sequence update:	November 1, 1991
Last modified:	May 1, 2013
This is version 134 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program