ID   PI3R6_HUMAN             Reviewed;         754 AA.
AC   Q5UE93; Q658R3;
DT   16-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT   07-DEC-2004, sequence version 1.
DT   03-AUG-2022, entry version 121.
DE   RecName: Full=Phosphoinositide 3-kinase regulatory subunit 6;
DE   AltName: Full=Phosphoinositide 3-kinase gamma adapter protein of 87 kDa;
DE   AltName: Full=p84 PI3K adapter protein;
DE            Short=p84 PIKAP;
DE   AltName: Full=p87 PI3K adapter protein;
DE            Short=p87PIKAP;
GN   Name=PIK3R6; Synonyms=C17orf38;
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].
RX   PubMed=16476736; DOI=10.1074/jbc.m512502200;
RA   Voigt P., Dorner M.B., Schaefer M.;
RT   "Characterization of p87PIKAP, a novel regulatory subunit of
RT   phosphoinositide 3-kinase gamma that is highly expressed in heart and
RT   interacts with PDE3B.";
RL   J. Biol. Chem. 281:9977-9986(2006).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16625196; DOI=10.1038/nature04689;
RA   Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA   Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA   Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA   Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA   DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA   Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA   Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA   LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA   Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA   Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA   Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA   Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA   Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT   "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT   human lineage.";
RL   Nature 440:1045-1049(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 703-753.
RC   TISSUE=Stomach;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [4]
RP   FUNCTION, AND INTERACTION WITH PDE3B AND RAPGEF3.
RX   PubMed=21393242; DOI=10.1074/jbc.m110.217026;
RA   Wilson L.S., Baillie G.S., Pritchard L.M., Umana B., Terrin A., Zaccolo M.,
RA   Houslay M.D., Maurice D.H.;
RT   "A phosphodiesterase 3B-based signaling complex integrates exchange protein
RT   activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human
RT   arterial endothelial cells.";
RL   J. Biol. Chem. 286:16285-16296(2011).
CC   -!- FUNCTION: Regulatory subunit of the PI3K gamma complex. Acts as an
CC       adapter to drive activation of PIK3CG by beta-gamma G protein dimers.
CC       The PIK3CG:PIK3R6 heterodimer is much less sensitive to beta-gamma G
CC       protein dimers than PIK3CG:PIK3R5 and its membrane recruitment and
CC       beta-gamma G protein dimer-dependent activation requires HRAS bound to
CC       PIK3CG. Recruits of the PI3K gamma complex to a PDE3B:RAPGEF3 signaling
CC       complex involved in angiogenesis; signaling seems to involve RRAS.
CC       {ECO:0000269|PubMed:21393242}.
CC   -!- SUBUNIT: Heterodimer of a catalytic subunit (PIK3CG) and a regulatory
CC       (PIK3R6) subunit. The binding of PIK3R6 to PIK3CG may exclude the
CC       binding of PIK3R5 to PIK3CG. Interacts with beta-gamma G protein dimers
CC       (By similarity). Interacts with PDE3B and RAPGEF3; form a signaling
CC       complex that regulates phosphatidylinositol 3-kinase gamma in
CC       angiogenesis (PubMed:21393242). {ECO:0000250|UniProtKB:Q3U6Q4,
CC       ECO:0000269|PubMed:21393242}.
CC   -!- INTERACTION:
CC       Q5UE93; Q13370: PDE3B; NbExp=3; IntAct=EBI-6172907, EBI-6172856;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q3U6Q4}. Cell
CC       membrane {ECO:0000250|UniProtKB:Q3U6Q4}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:Q3U6Q4}. Note=Translocated to the plasma
CC       membrane in a Ras-dependent manner. {ECO:0000250|UniProtKB:Q3U6Q4}.
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DR   EMBL; AY753192; AAV30085.1; -; mRNA.
DR   EMBL; AC003695; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC009451; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL833037; CAH56340.1; -; mRNA.
DR   CCDS; CCDS73985.1; -.
DR   RefSeq; NP_001010855.1; NM_001010855.3.
DR   RefSeq; XP_016879718.1; XM_017024229.1.
DR   AlphaFoldDB; Q5UE93; -.
DR   SMR; Q5UE93; -.
DR   BioGRID; 127016; 17.
DR   ComplexPortal; CPX-5987; Phosphatidylinositol 3-kinase complex class IB, p110gamma/p87.
DR   IntAct; Q5UE93; 10.
DR   STRING; 9606.ENSP00000480157; -.
DR   iPTMnet; Q5UE93; -.
DR   PhosphoSitePlus; Q5UE93; -.
DR   BioMuta; PIK3R6; -.
DR   DMDM; 74746772; -.
DR   EPD; Q5UE93; -.
DR   jPOST; Q5UE93; -.
DR   MassIVE; Q5UE93; -.
DR   PeptideAtlas; Q5UE93; -.
DR   PRIDE; Q5UE93; -.
DR   ProteomicsDB; 65246; -.
DR   Antibodypedia; 74162; 99 antibodies from 26 providers.
DR   DNASU; 146850; -.
DR   Ensembl; ENST00000619866.5; ENSP00000480157.1; ENSG00000276231.5.
DR   GeneID; 146850; -.
DR   KEGG; hsa:146850; -.
DR   MANE-Select; ENST00000619866.5; ENSP00000480157.1; NM_001010855.4; NP_001010855.1.
DR   UCSC; uc032etf.1; human.
DR   CTD; 146850; -.
DR   GeneCards; PIK3R6; -.
DR   HGNC; HGNC:27101; PIK3R6.
DR   HPA; ENSG00000276231; Tissue enhanced (lymphoid).
DR   MIM; 611462; gene.
DR   neXtProt; NX_Q5UE93; -.
DR   OpenTargets; ENSG00000276231; -.
DR   PharmGKB; PA162399570; -.
DR   VEuPathDB; HostDB:ENSG00000276231; -.
DR   eggNOG; ENOG502QSK4; Eukaryota.
DR   GeneTree; ENSGT00530000063753; -.
DR   HOGENOM; CLU_023662_0_0_1; -.
DR   InParanoid; Q5UE93; -.
DR   OMA; QQPVYFN; -.
DR   OrthoDB; 171539at2759; -.
DR   PhylomeDB; Q5UE93; -.
DR   BioCyc; MetaCyc:ENSG00000174083-MON; -.
DR   PathwayCommons; Q5UE93; -.
DR   Reactome; R-HSA-114604; GPVI-mediated activation cascade.
DR   Reactome; R-HSA-1660499; Synthesis of PIPs at the plasma membrane.
DR   Reactome; R-HSA-392451; G beta:gamma signalling through PI3Kgamma.
DR   SignaLink; Q5UE93; -.
DR   BioGRID-ORCS; 146850; 7 hits in 238 CRISPR screens.
DR   ChiTaRS; PIK3R6; human.
DR   GenomeRNAi; 146850; -.
DR   Pharos; Q5UE93; Tbio.
DR   PRO; PR:Q5UE93; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; Q5UE93; protein.
DR   Bgee; ENSG00000276231; Expressed in granulocyte and 92 other tissues.
DR   ExpressionAtlas; Q5UE93; baseline and differential.
DR   Genevisible; Q5UE93; HS.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR   GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; IBA:GO_Central.
DR   GO; GO:0005943; C:phosphatidylinositol 3-kinase complex, class IA; IC:ComplexPortal.
DR   GO; GO:0005944; C:phosphatidylinositol 3-kinase complex, class IB; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0046935; F:1-phosphatidylinositol-3-kinase regulator activity; ISS:UniProtKB.
DR   GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; IEA:Ensembl.
DR   GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR   GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0006955; P:immune response; IC:ComplexPortal.
DR   GO; GO:0045766; P:positive regulation of angiogenesis; IMP:UniProtKB.
DR   GO; GO:0043406; P:positive regulation of MAP kinase activity; ISS:UniProtKB.
DR   GO; GO:0045582; P:positive regulation of T cell differentiation; IEA:Ensembl.
DR   GO; GO:0042269; P:regulation of natural killer cell mediated cytotoxicity; IDA:CACAO.
DR   InterPro; IPR019522; PIK3R5/6.
DR   PANTHER; PTHR15593; PTHR15593; 1.
DR   Pfam; PF10486; PI3K_1B_p101; 3.
PE   1: Evidence at protein level;
KW   Angiogenesis; Cell membrane; Cytoplasm; Membrane; Reference proteome.
FT   CHAIN           1..754
FT                   /note="Phosphoinositide 3-kinase regulatory subunit 6"
FT                   /id="PRO_0000234338"
FT   REGION          343..363
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ   SEQUENCE   754 AA;  84258 MW;  B7E3F1C2D422E2E6 CRC64;
     MESSDVELDL QRSVQAVLRE LSTQAPALQS NQGMWRWSLH KKVERDPGKS PVLVRILLRE
     LEKAESQDLR HVIIPLLHTV MYVLTKATGI TEELYQRIYA FCTRLLTLPT PYCTVALDCA
     IRLKTEMAVP GTLYQRMVIA EQNLTNELYP YQERVFLFVD PELVSASVCS ALLLEIEAAQ
     AQQTPETCMR HVVSHALQAA LGEACHAGAL HRKLQASPRR TLEHYFHAVV AALEQMASEA
     SPSREGHVER LEEIYCSLLG PAAGRCGGDL VQERPPSIPL PSPYITFHLW TGEEQLWKEL
     VLFLRPRSQL RLSADLEVLD LQGLRPDREL ARVSVLSTDS GIERDLPTGA DELPAPGSPE
     MERAGLQRKG GIKKRAWPLD FLMPGSWDGP PGLHRRTGRP SGDGEMLPGV SRLHTARVLV
     LGDDRMLGRL AQAYHRLRKR ETQKFCLTPR LSLQLYYIPV LAPEKPAASR QPELGELATF
     LGRVDPWYQS NVNTLCPAIH KLAEMPPSLD TSRTVDPFIL DVITYYIRMG TQPIYFQIYT
     VKIFFSDLSQ DPTEDIFLIE LKVKIQDSKF PKDGFSPRRR GVAEGPGAEL SLCYQKALLS
     HRPREVTVSL RATGLILKAI PASDTEVSGS SHCPLPAAPV TDHTCLNVNV TEVVKSSNLA
     GKSFSTVTNT FRTNNIQIQS RDQRLLTLSL DKDDQRTFRD VVRFEVAPCP EPCSGAQKSK
     APWLNLHGQQ EVEAIKAKPK PLLMPINTFS GIVQ