Atlas of Genetics and Cytogenetics in Oncology and Haematology

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PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha))

Identity

Other namesGRB1
p85
p85-ALPHA
HGNC (Hugo) PIK3R1
LocusID (NCBI) 5295
Location 5q13.1
Location_base_pair Starts at 67588396 and ends at 67597649 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  (a) Schematic representation of the genomic organization of human PIK3R1. Exons are depicted as boxes. The length (bp) of introns and exons is shown (top and bottom respectively). (b) PIK3R1 undergoes alternative splicing to produce four major transcript variants. The exons that comprise each transcript are indicated, relative to the genomic organization illustrated in panel (a).
Description The human PIK3R1 gene encompasses 86102 bp of DNA and contains 16 exons.
Transcription Human PIK3R1 is alternatively spliced, resulting in four major protein-encoding transcripts.
Transcript variant 1: 7011 bp in length; the open-reading frame of the coding sequence is 2175 bp.
Transcript variant 2: 2439 bp in length; the open-reading frame of the coding sequence is 1365 bp.
Transcript variant 3: 2625 bp in length; the open-reading frame of the coding sequence is 1275 bp.
Transcript variant 4: 2473 bp in length; the open-reading frame of the coding sequence is 1086 bp.
Pseudogene None known.

Protein

Note Crystal structures have been reported for the p85α-SH3 domain (Liang et al., 1996), the p85α-BH domain (Musacchio et al., 1996), the nSH2 domain (Nolte et al., 1996), and the p85α-cSH2 domain (Hoedemaeker et al., 1999). Co-crystal structures have been reported for the p85α-niSH2 domain (residues 322-600) in complex with p110α (Huang et al., 1997), and for the human p85α-iSH2 domain in complex with the bovine p110α-ABD domain (Miled et al., 2007).
 
  Domain structure of four protein isoforms encoded by alternative splicing of PIK3R1. Abbreviations: SH3 domain, SRC homology 3 domain; BH domain, breakpoint cluster region homology-domain; nSH2, N-terminal SRC homology 2 domain; iSH2, inter- SRC homology 2 domain; c-SH2, C-terminal SRC homology 2 domain. Proline-rich regions separate the SH3 and BH domains, as well as the BH and nSH2 domains.
Description Isoforms: PIK3R1 encodes four distinct protein isoforms (CCDS3993 (p85α), CCDS3994 (p55α), CCDS3995 (p50α), and CCDS56374) as a result of alternative splicing (Inukai et al., 1997).
p85α: p85α has an SH3 domain, a BCR-homology (BH) domain, and nSH2, iSH2, and cSH2 domains. The SH3 domain of p85α mediates binding to FAK, CAS, Apoptin, Ruk, SNX9, Dynamin, Cbl, and BCR-ABL (reviewed in Mellor et al., 2012). The BH domain of p85α mediates binding to XB-1, Rac, Cdc42, Rab5, PTEN (reviewed in Mellor et al., 2012). The nSH2 domain of p85α interacts with the helical domain of p110α (Miled et al., 2007). The iSH2 domain of p85α interacts with both the ABD and C2 domains of p110α leading, respectively, to stabilization and inhibition of p110α (Dhand et al., 1994; Fu et al., 2004; Elis et al., 2006; Huang et al., 2007). Residues D560 and N564 in the p85α-iSH2 domain are within hydrogen bonding distance of residue N345 of the p110α-C2 domain (Huang et al., 2007). This interaction is required for the inhibition of p110α (Wu et al., 2009). It has been suggested that residues 447-561 within the iSH2 might form contact with the plasma membrane (Huang et al., 2007). The nSH2 and cSH2 domains of p85α mediate binding to phosphotyrosine residues in certain receptor tyrosine kinase and adaptor proteins, in the context of a pYXXM motif.
p55α: Has a unique amino terminal region of 34 amino acids. Compared to p85α, p55α lacks the amino terminal SH3 and BH domains but shares the C-terminal nSH2, iSH2, and cSH2 domains (Inuki et al., 1997).
p50α: Has a unique amino terminal region of 6 amino acids. Compared to p85α, p50α lacks the amino terminal SH3 and BH domains but shares the C-terminal nSH2, iSH2, and cSH2 domains (Inuki et al., 1997).
Isoform-4: The shortest isoform. Lacks the first 398 amino acids of p85α but is identical to p85α throughout the remainder of the protein.
Expression In mammalian tissues, p85α is expressed in brain, liver, muscle, fat, kidney, and spleen; p55α is expressed predominantly in brain and skeletal muscle; and p50α is expressed in brain, liver, and kidney (Antonetti et al., 1996; Inuki et al., 1996; Inuki et al.,1997; Geering et al., 2007).
Localisation Intracellular; plasma membrane; cytoplasm.
Function Regulation of PI3K signaling by p85α: p85α is the regulatory subunit of PI3K. In quiescent cells, p85α binds to p110α, the catalytic subunit of PI3K, and both stabilizes p110α and inhibits the basal activity of p110α. Ligand-induced phosphorylation of receptor tyrosine kinases or adaptor proteins on tyrosine residues, within a pYXXM motif, facilitates the binding of p85α to the phosphotyrosine residues via its SH2 domains. Consequently, the inhibitory effect of p85α on p110α is relieved and PI3K is brought into the vicinity of the plasma membrane where it catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 in turn recruits the AKT (v-akt murine thymoma viral oncogene homolog) serine-threonine kinase and the PDK1 (phosphoinositide-dependent protein kinase 1) kinase to the plasma membrane, thus facilitating the phosphorylation and activation of AKT. Once activated, AKT can initiate several downstream signal transduction cascades that regulate protein synthesis, cell survival, cell growth and metabolism, and the cell cycle (Reviewed in Vanhaesebroeck et al., 2010).
Under conditions of nutrient deprivation, p85α is phosphorylated by IKK on serine-690. Consequently, the ability of p85α to bind phosphotyrosine proteins is reduced and PI3K-AKT signaling is diminished (Comb et al., 2012). Similarly, the activation of PKC family members by phorbol ester stimulation results in phosphorylation of p85α on serine-361 and serine-652, and leads to reduced binding of p85α to phosphotyrosines and inhibition of PI3K-AKT signaling (Lee et al., 2011).

Regulation of PTEN by p85α: The PI3K-AKT signal transduction pathway is antagonized by the activity of the PTEN phosphatase, which dephosphorylates PIP3 to generate PIP2. Chagpar et al., (2010) demonstrated that p85α binds directly to PTEN via the p85α-SH3-BH domains. Cells expressing a synthetic mutant of p85α that abolished the p85α-PTEN interaction exhibited increased AKT activation following stimulation by growth factors. Chagpar et al., thus proposed that p85α can bind to PTEN and enhance PTEN activity. Subsequently, Cheung et al., (2011) demonstrated that compared to wildtype p85α, a tumor-associated mutant (p85α-E160X) that introduces a premature stop codon within the BH domain, was associated with reduced stability of the PTEN protein. Treatment of cells expressing the p85α-E160X mutant with a proteosome inhibitor lead to a modest increase in PTEN levels, further suggesting that the p85α-PTEN interaction prevents proteosomal degradation of PTEN and thus increases PTEN stability. The regulation of PTEN activity by p85α accounts for the increased insulin sensitivity observed in PIK3R1-/- or p85α-/- mice (Mauvais-Jarvis et al., 2002; Brachmann et al., 2005; Taniguchi et al., 2006; Taniguchi et al., 2010; Chagpar et al., 2010).

Receptor trafficking: p85α has GAP (GTP-ase Activating Protein) activity towards the Rab4, Rab5, Rac1, and Cdc42 small GTPases and, to a lesser extent, towards the Rab6 GTPase. The GAP activity of p85α resides within the BH domain. Within the BH domain, Arg151 and Arg274 are important for maximal GAP activity of p85α. The regulation of Rab4 and Rab5 activity by p85α has been implicated in the endosomal trafficking of activated PDGFR; cells expressing a synthetic mutant (p85α-Arg274A) exhibited delayed degradation of activated PDGFR, prolonged activation of the MAPK and AKT signalling pathways, and the capacity to transform NIH 3T3 cells (Chamberlain et al., 2004; Chamberlain et al., 2008; Chamberlain et al., 2010).

Regulation of the unfolded protein response: p85α interacts with XBP-1s, a transcription factor that regulates the unfolded protein response following endoplasmic reticulum stress, and facilitates the relocation of XBP-1s to the nucleus (Park et al., 2010a; Winnay et al., 2010).

p55α and p50α isoforms: Involved in insulin signaling (Inuki et al., 1997; Chen et al., 2004).

Homology Homologues of H. sapiens PIK3R1 exist in P. troglodytes (99.9% amino acid identity), M. mulatta (99.2% amino acid identity), C. lupus (95.7% amino acid identity), B. taurus (96.8% amino acid identity), M. musculus (96.0% amino acid identity), R. norvegicus (94.2% amino acid identity), G. gallus (89.1% amino acid identity), D. rerio (79.3% amino acid identity), and C. elegans (33.8% amino acid identity).

Mutations

Note A polymorphic variant of PIK3R1 (Met326Ile; rs3730089), has been described (Baier et al., 1998; Almind et al., 2002). The PIK3R1-Ile326 allele has been reported to be associated with increased risk to colon cancer in a population based case-control study (Li et al., 2008).
 
  Distribution of somatic mutations in PIK3R1 relative to the functional domains of p85α. Mutation data are displayed by cancer site, and were obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC v59 release, May 23rd 2012) (Forbes et al., 2010). Each square represents a single mutation. Nonsense mutations and frameshift mutations (pink squares) are distinguished from missense mutations (turquoise squares) and in-frame insertions/deletions (green squares).
Germinal A germline mutation in exon 6 of PIK3R1 has been described in a patient with agammaglobulinemia and an absence of B lineage cells (Conley et al., 2012). The mutation (p85α-W298X) resulted in loss of p85α expression, but did not affect p55α or p50α. The patient was homozygous for the mutation; her parents were both heterozygous carriers.
Somatic Somatic mutations in PIK3R1 have been found in endometrial cancers (26%, 34 of 133), cancers of the central nervous system (4%, 26 of 657) and of the large intestine (5%, 19 of 355), ovarian cancer (2%, 5 of 257), breast cancer (2%, 10 of 500), urothelial cancer (0.7%, 1 of 145), squamous cell carcinoma of the skin (11%, 1 of 9), pancreatic cancer (2%, 1 of 53), and in hematological malignancy (1%, 3 of 472) (Philp et al., 2001; Mizoughi et al., 2004; Shi et al., 2006; Sjoblom et al., 2006; Jones et al., 2008; Parsons et al., 2008; The Cancer Genome Research Atlas Network, 2008; Bittinger et al., 2009; Jaiswal et al., 2009; Forbes et al., 2010; Bettegowda et al., 2011; Kan et al., 2010; Park et al., 2010b; Parsons et al., 2011; Cheung et al., 2011; Sjodahl et al., 2011; The Cancer Genome Atlas Research Network, 2011; Urick et al., 2011; Lipson et al., 2012; Shah et al., 2012).

Mutation spectrum: Among 107 nonsynonymous, somatic mutations of PIK3R1 catalogued in the COSMIC database (v59 release, May 23rd, 2012) (Forbes et al., 2010), 43% (46 of 107) of mutations are in-frame insertions/deletions, 14% (15 of 107) are nonsense mutations, 11.2% (12 of 107) are frameshift mutations, 31.8% (34 of 107) are missense mutations. The majority (68.2%, 73 of 107) of all somatic mutations in PIK3R1 localize to animo acid residues within the iSH2 domain, which is shared by all four protein isoforms encoded by PIK3R1.

Altered functional properties of mutant proteins: Biochemical and cellular studies of tumor-associated p85α mutants have revealed functional differences between mutant p85α and wild type p85α, as well as functional differences among various p85α mutants (Philp et al., 2001; Jaiswal et al., 2009; Sun et al., 2010; Cheung et al., 2011; Urick et al., 2011).

- Transforming properties: Sun et al., (2010) evaluated the ability of nine tumor-associated mutant p85α proteins to transform chicken embryo fibroblasts. The p85α-KS459delN and p85α-DKRMNS560del mutants had the highest efficiency of transformation, the p85α-R574fs and p85α-T576del mutants had intermediate efficiency of transformation, and the p85α-D560Y, p85α-N564K p85α-W583del, p85α-E439del, and p85α-G376R mutants were only weakly tansforming (Sun et al., 2010). Transformation was mediated by p110α but not by p110α, p110α, or p110α (Sun et al., 2010). Each of the nine p85α mutants analyzed by Sun et al., retained the ability to bind p110α and resulted in hyperphosphorylation of AKT (T308) and 4E-BP1 when exogenously expressed in CEF cells (Sun et al., 2010). Eight of the tumor-associated mutants analyzed by Sun et al., (2010) localized to the iSH2 domain; one mutant (p85α-G376R) localized to the nSH2 domain. Jaiswal et al., showed that the p85α-D560Y, p85α-N564D, and p85α-QYL579delL mutants were capable of promoting both the IL-3 independent growth and anchorage-independent growth of BaF3 cells (Jaiswal et al., 2009). Similarily, Cheung et al., showed that the p85α-R574fs, p85α-T576del, p85α-E160X, p85α-R348X, and p85α-R503W mutants induced IL3-independent growth of BaF3 cells (Cheung et al., 2011).

- Altered p110α-binding: Truncating mutants of p85α that lack all or part of the the iSH2 domain (p85α-E160X, p85α-R162X, p85α-L380fs, p85α-R348X, p85α-K511VfsX2) fail to bind to p110α (Jaiswal et al., 2009; Cheung et al., 2011; Urick et al., 2011). In contrast, small in-frame deletions or missense mutations within the iSH2 domain retained the ability to bind p110α (Jaiswal et al., 2009; Cheung et al., 2011; Urick et al., 2011).

- Increased PI3K activity: Jaiswal et al., (2009) showed that p85α mutants that were capable of binding p110α were able to stabilize p110α. p85α/p110α holoenzymes composed of the p85α-N564 or p85α-QYL579delL mutants had increased lipid kinase activity compared with the wildtype-p85α/p110α holoenzyme (Jaiswal et al., 2009). Holoenzymes consisting of mutant p85α and p110α or p110α also exhibited increased kinase activity (Jaiswal et al., 2009). Philp et al. (2001) described a recurrent intronic PIK3R1 mutation in ovarian cancer cells; the mutation caused skipping of exon 13, resulting in deletion of residues 551-670 within the iSH2/cSH2 domains of p85α, and was associated with increased PI3K activity.

- Hyperphosphorylation of AKT: Mutants of p85α that retained the ability to bind p110α also lead to increased phosphorylation of AKT (Jaiswal et al., 2009; Cheung et al., 2011; Urick et al., 2011).

- Dysregulation of PTEN stability: Cheung et al., (2011) showed that the p85α-E160X mutant, which was present in an endometrial tumor and truncates p85α within the BH domain, is associated with reduced stability of the PTEN protein.

Implicated in

Entity Endometrial cancer
Oncogenesis Somatic mutations in PIK3R1 have been observed in 19%-43% of endometrioid endometrial carcinomas (Cheung et al., 2011; Urick et al., 2011), in 8% of serous endometrial carcinomas (Urick et al., 2011), in 20% of clear cell endometrial carcinomas (Urick et al., 2011), and in 6% of endometrial carcinosarcomas (Cheung et al., 2011). Mutations in PIK3R1 tended to be mutually exclusive with mutations in PIK3CA, which encodes the catalytic subunit of PI3K, but co-occurred with mutations in PTEN, and KRAS (Cheung et al., 2011; Urick et al., 2011).
  
Entity Glioblastoma
Oncogenesis Somatic mutations in PIK3R1 have been reported in 7% (20 of 276) of glioblastomas (Mizoughi et al., 2004; Parsons et al., 2008; The Cancer Genome Research Atlas Network, 2008; Park et al., 2010b). No amplification or overexpression of PIK3R1 was observed among 103 glioblastomas (Knobbe et al., 2003).
  
Entity Colorectal cancer
Oncogenesis Somatic mutations in PIK3R1 have been reported in 4% (10 of 228) of colorectal cancers (Philp et al., 2001; Jaiswal et al., 2009; Park et al., 2010b), and in a colorectal cancer cell line (Shi et al., 2006).
  
Entity Ovarian cancer
Oncogenesis Somatic mutations in PIK3R1 have been reported in 2% (5 of 257) of ovarian cancers (Philp et al., 2001; Jaiswal et al., 2009; Kan et al., 2010; Park et al., 2010b; The Cancer Genome Atlas Research Network, 2011).
  
Entity Breast cancer
Oncogenesis Somatic mutations in PIK3R1 have been reported in 2% (10 of 500) of breast cancers (Sjoblom et al., 2006; Jaiswal et al., 2009; Kan et al., 2010; Park et al., 2010b; Jiao et al., 2012; Shah et al., 2012).
  
Entity Urothelial cancer
Oncogenesis Somatic mutations in PIK3R1 have been reported in 0.7% (1 of 145) of urothelial cancers (Sjodahl et al., 2011).
  
Entity Squamous cell carcinoma of the skin
Oncogenesis Somatic mutations in PIK3R1 have been reported in 8% (1 of 9) squamous cell carcinoma of the skin (Park et al., 2010b).
  
Entity Pancreatic cancer
Oncogenesis Somatic mutations in PIK3R1 have been reported in 16% (1 of 53) of pancreatic cancers (Jones et al., 2008; Jaiswal et al., 2009; Kan et al., 2010).
  
Entity Various human cancers
Oncogenesis By expression profiling, reduced expression of PIK3R1 has been noted in cancers of the prostate, lung, bladder, ovary, breast, and liver (Taniguchi et al., 2010).
  

External links

Nomenclature
HGNC (Hugo)PIK3R1   8979
Cards
AtlasPIK3R1ID41717ch5q13
Entrez_Gene (NCBI)PIK3R1  5295  phosphoinositide-3-kinase, regulatory subunit 1 (alpha)
GeneCards (Weizmann)PIK3R1
Ensembl hg19 (Hinxton)ENSG00000145675 [Gene_View]  chr5:67588396-67597649 [Contig_View]  PIK3R1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000145675 [Gene_View]  chr5:67588396-67597649 [Contig_View]  PIK3R1 [Vega]
ICGC DataPortalENSG00000145675
cBioPortalPIK3R1
AceView (NCBI)PIK3R1
Genatlas (Paris)PIK3R1
WikiGenes5295
SOURCE (Princeton)PIK3R1
Genomic and cartography
GoldenPath hg19 (UCSC)PIK3R1  -     chr5:67588396-67597649 +  5q13.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PIK3R1  -     5q13.1   [Description]    (hg38-Dec_2013)
EnsemblPIK3R1 - 5q13.1 [CytoView hg19]  PIK3R1 - 5q13.1 [CytoView hg38]
Mapping of homologs : NCBIPIK3R1 [Mapview hg19]  PIK3R1 [Mapview hg38]
OMIM171833   269880   615214   
Gene and transcription
Genbank (Entrez)AF279367 AI124626 AI334281 AK000121 AK094785
RefSeq transcript (Entrez)NM_001242466 NM_181504 NM_181523 NM_181524
RefSeq genomic (Entrez)AC_000137 NC_000005 NC_018916 NG_012849 NT_034772 NW_001838935 NW_004929322
Consensus coding sequences : CCDS (NCBI)PIK3R1
Cluster EST : UnigeneHs.734132 [ NCBI ]
CGAP (NCI)Hs.734132
Alternative Splicing : Fast-db (Paris)GSHG0023985
Alternative Splicing GalleryENSG00000145675
Gene ExpressionPIK3R1 [ NCBI-GEO ]     PIK3R1 [ SEEK ]   PIK3R1 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP27986 (Uniprot)
NextProtP27986  [Medical]
With graphics : InterProP27986
Splice isoforms : SwissVarP27986 (Swissvar)
Domaine pattern : Prosite (Expaxy)RHOGAP (PS50238)    SH2 (PS50001)    SH3 (PS50002)   
Domains : Interpro (EBI)PI3kinase_P85    Rho_GTPase_activation_prot    RhoGAP_dom    SH2    SH3_2    SH3_domain   
Related proteins : CluSTrP27986
Domain families : Pfam (Sanger)RhoGAP (PF00620)    SH2 (PF00017)    SH3_2 (PF07653)   
Domain families : Pfam (NCBI)pfam00620    pfam00017    pfam07653   
Domain families : Smart (EMBL)RhoGAP (SM00324)  SH2 (SM00252)  SH3 (SM00326)  
DMDM Disease mutations5295
Blocks (Seattle)P27986
PDB (SRS)1A0N    1AZG    1H9O    1PBW    1PHT    1PIC    1PKS    1PKT    2IUG    2IUH    2IUI    2RD0    2V1Y    3HHM    3HIZ    3I5R    3I5S    4A55    4JPS    4L1B    4L23    4L2Y   
PDB (PDBSum)1A0N    1AZG    1H9O    1PBW    1PHT    1PIC    1PKS    1PKT    2IUG    2IUH    2IUI    2RD0    2V1Y    3HHM    3HIZ    3I5R    3I5S    4A55    4JPS    4L1B    4L23    4L2Y   
PDB (IMB)1A0N    1AZG    1H9O    1PBW    1PHT    1PIC    1PKS    1PKT    2IUG    2IUH    2IUI    2RD0    2V1Y    3HHM    3HIZ    3I5R    3I5S    4A55    4JPS    4L1B    4L23    4L2Y   
PDB (RSDB)1A0N    1AZG    1H9O    1PBW    1PHT    1PIC    1PKS    1PKT    2IUG    2IUH    2IUI    2RD0    2V1Y    3HHM    3HIZ    3I5R    3I5S    4A55    4JPS    4L1B    4L23    4L2Y   
Human Protein AtlasENSG00000145675
Peptide AtlasP27986
HPRD01381
IPIIPI00021448   IPI00295788   IPI00333040   IPI00807573   IPI00976156   IPI00984521   IPI00983629   IPI00984326   IPI00974572   IPI00976803   IPI00983869   
Protein Interaction databases
DIP (DOE-UCLA)P27986
IntAct (EBI)P27986
FunCoupENSG00000145675
BioGRIDPIK3R1
IntegromeDBPIK3R1
STRING (EMBL)PIK3R1
Ontologies - Pathways
QuickGOP27986
Ontology : AmiGOnegative regulation of cell-matrix adhesion  transmembrane receptor protein tyrosine kinase adaptor activity  insulin receptor binding  insulin-like growth factor receptor binding  neurotrophin TRKA receptor binding  protein binding  cytosol  plasma membrane  phosphatidylinositol 3-kinase complex  1-phosphatidylinositol-4-phosphate 3-kinase, class IA complex  protein phosphorylation  phospholipid metabolic process  phosphatidylinositol biosynthetic process  epidermal growth factor receptor signaling pathway  blood coagulation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  extrinsic apoptotic signaling pathway via death domain receptors  intrinsic apoptotic signaling pathway in response to DNA damage  phosphatidylinositol 3-kinase signaling  membrane  viral process  protein phosphatase binding  platelet activation  B cell differentiation  positive regulation of cell migration  T cell costimulation  positive regulation of tumor necrosis factor production  cellular response to UV  phosphatidylinositol 3-kinase regulator activity  Fc-epsilon receptor signaling pathway  Fc-gamma receptor signaling pathway involved in phagocytosis  negative regulation of apoptotic process  ErbB-3 class receptor binding  phosphatidylinositol 3-kinase binding  regulation of phosphatidylinositol 3-kinase activity  insulin binding  insulin receptor substrate binding  small molecule metabolic process  innate immune response  negative regulation of osteoclast differentiation  positive regulation of transcription from RNA polymerase II promoter  positive regulation of glucose import  phosphatidylinositol phosphorylation  insulin-like growth factor receptor signaling pathway  insulin-like growth factor receptor signaling pathway  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  T cell receptor signaling pathway  leukocyte migration  NFAT protein import into nucleus  growth hormone receptor signaling pathway  positive regulation of establishment of protein localization to plasma membrane  
Ontology : EGO-EBInegative regulation of cell-matrix adhesion  transmembrane receptor protein tyrosine kinase adaptor activity  insulin receptor binding  insulin-like growth factor receptor binding  neurotrophin TRKA receptor binding  protein binding  cytosol  plasma membrane  phosphatidylinositol 3-kinase complex  1-phosphatidylinositol-4-phosphate 3-kinase, class IA complex  protein phosphorylation  phospholipid metabolic process  phosphatidylinositol biosynthetic process  epidermal growth factor receptor signaling pathway  blood coagulation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  extrinsic apoptotic signaling pathway via death domain receptors  intrinsic apoptotic signaling pathway in response to DNA damage  phosphatidylinositol 3-kinase signaling  membrane  viral process  protein phosphatase binding  platelet activation  B cell differentiation  positive regulation of cell migration  T cell costimulation  positive regulation of tumor necrosis factor production  cellular response to UV  phosphatidylinositol 3-kinase regulator activity  Fc-epsilon receptor signaling pathway  Fc-gamma receptor signaling pathway involved in phagocytosis  negative regulation of apoptotic process  ErbB-3 class receptor binding  phosphatidylinositol 3-kinase binding  regulation of phosphatidylinositol 3-kinase activity  insulin binding  insulin receptor substrate binding  small molecule metabolic process  innate immune response  negative regulation of osteoclast differentiation  positive regulation of transcription from RNA polymerase II promoter  positive regulation of glucose import  phosphatidylinositol phosphorylation  insulin-like growth factor receptor signaling pathway  insulin-like growth factor receptor signaling pathway  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  T cell receptor signaling pathway  leukocyte migration  NFAT protein import into nucleus  growth hormone receptor signaling pathway  positive regulation of establishment of protein localization to plasma membrane  
Pathways : BIOCARTAThe Co-Stimulatory Signal During T-cell Activation [Genes]    Tumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes]    Human Cytomegalovirus and Map Kinase Pathways [Genes]    The IGF-1 Receptor and Longevity [Genes]    PDGF Signaling Pathway [Genes]    Thrombin signaling and protease-activated receptors [Genes]    mTOR Signaling Pathway [Genes]    TPO Signaling Pathway [Genes]    Role of Erk5 in Neuronal Survival [Genes]    Corticosteroids and cardioprotection [Genes]    Transcription factor CREB and its extracellular signals [Genes]    Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway [Genes]    Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    Signaling of Hepatocyte Growth Factor Receptor [Genes]    Rac 1 cell motility signaling pathway [Genes]    AKT Signaling Pathway [Genes]    Role of PI3K subunit p85 in regulation of Actin Organization and Cell Migration [Genes]    EGF Signaling Pathway [Genes]    B Cell Survival Pathway [Genes]    Control of skeletal myogenesis by HDAC & calcium/calmodulin-dependent kinase (CaMK) [Genes]    Role of ERBB2 in Signal Transduction and Oncology [Genes]    Insulin Signaling Pathway [Genes]    T Cell Receptor Signaling Pathway [Genes]    VEGF, Hypoxia, and Angiogenesis [Genes]    CXCR4 Signaling Pathway [Genes]    Role of nicotinic acetylcholine receptors in the regulation of apoptosis [Genes]    Regulation of BAD phosphorylation [Genes]    Phospholipids as signalling intermediaries [Genes]    IGF-1 Signaling Pathway [Genes]    IL-7 Signal Transduction [Genes]    Nerve growth factor pathway (NGF) [Genes]    Phospholipase C Signaling Pathway [Genes]    Ras-Independent pathway in NK cell-mediated cytotoxicity [Genes]    Growth Hormone Signaling Pathway [Genes]    Inhibition of Cellular Proliferation by Gleevec [Genes]    NFAT and Hypertrophy of the heart (Transcription in the broken heart) [Genes]    Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha) [Genes]    Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages [Genes]    PTEN dependent cell cycle arrest and apoptosis [Genes]    CTCF: First Multivalent Nuclear Factor [Genes]    Ras Signaling Pathway [Genes]    Trefoil Factors Initiate Mucosal Healing [Genes]    Influence of Ras and Rho proteins on G1 to S Transition [Genes]    Regulation of eIF4e and p70 S6 Kinase [Genes]    Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation [Genes]    Trka Receptor Signaling Pathway [Genes]    Fc Epsilon Receptor I Signaling in Mast Cells [Genes]   
Pathways : KEGGErbB signaling pathway    Ras signaling pathway    Rap1 signaling pathway    Chemokine signaling pathway    HIF-1 signaling pathway    FoxO signaling pathway    Phosphatidylinositol signaling system    mTOR signaling pathway    PI3K-Akt signaling pathway    Apoptosis    Adrenergic signaling in cardiomyocytes    VEGF signaling pathway    Osteoclast differentiation    Focal adhesion    Toll-like receptor signaling pathway    Jak-STAT signaling pathway    Natural killer cell mediated cytotoxicity    T cell receptor signaling pathway    B cell receptor signaling pathway    Fc epsilon RI signaling pathway    Fc gamma R-mediated phagocytosis    TNF signaling pathway    Leukocyte transendothelial migration    Neurotrophin signaling pathway    Cholinergic synapse    Regulation of actin cytoskeleton    Insulin signaling pathway    Progesterone-mediated oocyte maturation    Estrogen signaling pathway    Prolactin signaling pathway    Thyroid hormone signaling pathway    Type II diabetes mellitus    Non-alcoholic fatty liver disease (NAFLD)    Aldosterone-regulated sodium reabsorption    Carbohydrate digestion and absorption    Bacterial invasion of epithelial cells    Chagas disease (American trypanosomiasis)    Toxoplasmosis    Amoebiasis    Hepatitis C    Hepatitis B    Measles    Influenza A    HTLV-I infection    Epstein-Barr virus infection    Pathways in cancer    Viral carcinogenesis    Proteoglycans in cancer    Colorectal cancer    Renal cell carcinoma    Pancreatic cancer    Endometrial cancer    Glioma    Prostate cancer    Melanoma    Chronic myeloid leukemia    Acute myeloid leukemia    Small cell lung cancer    Non-small cell lung cancer   
REACTOMEP27986 [protein]
REACTOME PathwaysREACT_111155 Cell-Cell communication [pathway]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_604 Hemostasis [pathway]
REACTOME PathwaysREACT_6900 Immune System [pathway]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabasePIK3R1
DoCM (Curated mutations)PIK3R1
Wikipedia pathwaysPIK3R1
Gene fusion - rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerPIK3R1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PIK3R1
dbVarPIK3R1
ClinVarPIK3R1
1000_GenomesPIK3R1 
Exome Variant ServerPIK3R1
SNP (GeneSNP Utah)PIK3R1
SNP : HGBasePIK3R1
Genetic variants : HAPMAPPIK3R1
Genomic VariantsPIK3R1  PIK3R1 [DGVbeta]
Mutations
ICGC Data PortalENSG00000145675 
Cancer Gene: CensusPIK3R1 
Somatic Mutations in Cancer : COSMICPIK3R1 
CONAN: Copy Number AnalysisPIK3R1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)5:67588396-67597649
Mutations and Diseases : HGMDPIK3R1
OMIM171833    269880    615214   
MedgenPIK3R1
NextProtP27986 [Medical]
GENETestsPIK3R1
Disease Genetic AssociationPIK3R1
Huge Navigator PIK3R1 [HugePedia]  PIK3R1 [HugeCancerGEM]
snp3D : Map Gene to Disease5295
DGIdb (Drug Gene Interaction db)PIK3R1
General knowledge
Homologs : HomoloGenePIK3R1
Homology/Alignments : Family Browser (UCSC)PIK3R1
Phylogenetic Trees/Animal Genes : TreeFamPIK3R1
Chemical/Protein Interactions : CTD5295
Chemical/Pharm GKB GenePA33312
Drug Sensitivity PIK3R1
Clinical trialPIK3R1
Cancer Resource (Charite)ENSG00000145675
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=PIK3R1
Probes
Litterature
PubMed498 Pubmed reference(s) in Entrez
CoreMinePIK3R1
GoPubMedPIK3R1
iHOPPIK3R1

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The p85alpha subunit of phosphatidylinositol 3'-kinase binds to and stimulates the GTPase activity of Rab proteins.
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p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity.
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The iSH2 domain of PI 3-kinase is a rigid tether for p110 and not a conformational switch.
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Arch Biochem Biophys. 2004 Dec 15;432(2):244-51.
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Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas.
Mizoguchi M, Nutt CL, Mohapatra G, Louis DN.
Brain Pathol. 2004 Oct;14(4):372-7.
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Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice.
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Mol Cell Biol. 2005 Mar;25(5):1596-607.
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Mutations in the inter-SH2 domain of the regulatory subunit of phosphoinositide 3-kinase: effects on catalytic subunit binding and holoenzyme function.
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PMID 17132102
 
Mutation of the PI3' kinase gene in a human colon carcinoma cell line, HCC2998.
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The consensus coding sequences of human breast and colorectal cancers.
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Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN.
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Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12093-7. Epub 2006 Jul 31.
PMID 16880400
 
Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers.
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Proc Natl Acad Sci U S A. 2007 May 8;104(19):7809-14. Epub 2007 Apr 30.
PMID 17470792
 
The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.
Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM.
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PMID 18079394
 
Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.
Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL.
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Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3-kinase results in cell transformation.
Chamberlain MD, Chan T, Oberg JC, Hawrysh AD, James KM, Saxena A, Xiang J, Anderson DH.
J Biol Chem. 2008 Jun 6;283(23):15861-8. Epub 2008 Apr 3.
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Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
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Science. 2008 Sep 26;321(5897):1801-6. Epub 2008 Sep 4.
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Association between phosphatidylinositol 3-kinase regulatory subunit p85alpha Met326Ile genetic polymorphism and colon cancer risk.
Li L, Plummer SJ, Thompson CL, Tucker TC, Casey G.
Clin Cancer Res. 2008 Feb 1;14(3):633-7. (REVIEW)
PMID 18245521
 
An integrated genomic analysis of human glioblastoma multiforme.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW.
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Comprehensive genomic characterization defines human glioblastoma genes and core pathways.
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Expression status and mutational analysis of the PTEN and P13K subunit genes in ovarian granulosa cell tumors.
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Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation.
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Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants.
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Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase.
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Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking.
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COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer.
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PMID 19906727
 
Diverse somatic mutation patterns and pathway alterations in human cancers.
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PMID 20668451
 
The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation.
Park SW, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K, Ozcan U.
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Somatic mutation of PIK3R1 gene is rare in common human cancers.
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Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.
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The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling.
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PMID 20530665
 
The emerging mechanisms of isoform-specific PI3K signalling.
Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B.
Nat Rev Mol Cell Biol. 2010 May;11(5):329-41. Epub 2010 Apr 9. (REVIEW)
PMID 20379207
 
A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response.
Winnay JN, Boucher J, Mori MA, Ueki K, Kahn CR.
Nat Med. 2010 Apr;16(4):438-45. Epub 2010 Mar 28.
PMID 20348923
 
Mutations in CIC and FUBP1 contribute to human oligodendroglioma.
Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, Rodriguez FJ, Cahill DP, McLendon R, Riggins G, Velculescu VE, Oba-Shinjo SM, Marie SK, Vogelstein B, Bigner D, Yan H, Papadopoulos N, Kinzler KW.
Science. 2011 Sep 9;333(6048):1453-5. Epub 2011 Aug 4.
PMID 21817013
 
High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability.
Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, Lu Y, Stemke-Hale K, Dyer MD, Zhang F, Ju Z, Cantley LC, Scherer SE, Liang H, Lu KH, Broaddus RR, Mills GB.
Cancer Discov. 2011 Jul;1(2):170-85. Epub 2011 Jun 7.
PMID 21984976
 
Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85alpha Src homology-2 domains.
Lee JY, Chiu YH, Asara J, Cantley LC.
Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14157-62. Epub 2011 Aug 8.
PMID 21825134
 
The genetic landscape of the childhood cancer medulloblastoma.
Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, Boca SM, Carter H, Samayoa J, Bettegowda C, Gallia GL, Jallo GI, Binder ZA, Nikolsky Y, Hartigan J, Smith DR, Gerhard DS, Fults DW, VandenBerg S, Berger MS, Marie SK, Shinjo SM, Clara C, Phillips PC, Minturn JE, Biegel JA, Judkins AR, Resnick AC, Storm PB, Curran T, He Y, Rasheed BA, Friedman HS, Keir ST, McLendon R, Northcott PA, Taylor MD, Burger PC, Riggins GJ, Karchin R, Parmigiani G, Bigner DD, Yan H, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE.
Science. 2011 Jan 28;331(6016):435-9. Epub 2010 Dec 16.
PMID 21163964
 
A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1.
Sjodahl G, Lauss M, Gudjonsson S, Liedberg F, Hallden C, Chebil G, Mansson W, Hoglund M, Lindgren D.
PLoS One. 2011 Apr 14;6(4):e18583.
PMID 21533174
 
Integrated genomic analyses of ovarian carcinoma.
Cancer Genome Atlas Research Network.
Nature. 2011 Jun 29;474(7353):609-15. doi: 10.1038/nature10166.
PMID 21720365
 
PIK3R1 (p85alpha) is somatically mutated at high frequency in primary endometrial cancer.
Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW.
Cancer Res. 2011 Jun 15;71(12):4061-7. Epub 2011 Apr 8.
PMID 21478295
 
p85alpha SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation.
Comb WC, Hutti JE, Cogswell P, Cantley LC, Baldwin AS.
Mol Cell. 2012 Mar 30;45(6):719-30. Epub 2012 Feb 16.
PMID 22342344
 
Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K.
Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E, Smith AM, Perez EE, Murray PJ.
J Exp Med. 2012 Mar 12;209(3):463-70. Epub 2012 Feb 20.
PMID 22351933
 
Somatic mutations in the Notch, NF-KB, PIK3CA, and Hedgehog pathways in human breast cancers.
Jiao X, Wood LD, Lindman M, Jones S, Buckhaults P, Polyak K, Sukumar S, Carter H, Kim D, Karchin R, Sjoblom T.
Genes Chromosomes Cancer. 2012 May;51(5):480-9. doi: 10.1002/gcc.21935. Epub 2012 Feb 3.
PMID 22302350
 
Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.
Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, Jarosz M, Curran JA, Balasubramanian S, Bloom T, Brennan KW, Donahue A, Downing SR, Frampton GM, Garcia L, Juhn F, Mitchell KC, White E, White J, Zwirko Z, Peretz T, Nechushtan H, Soussan-Gutman L, Kim J, Sasaki H, Kim HR, Park SI, Ercan D, Sheehan CE, Ross JS, Cronin MT, Janne PA, Stephens PJ.
Nat Med. 2012 Feb 12;18(3):382-4. doi: 10.1038/nm.2673.
PMID 22327622
 
Multiple roles for the p85alpha isoform in the regulation and function of PI3K signalling and receptor trafficking.
Mellor P, Furber LA, Nyarko JN, Anderson DH.
Biochem J. 2012 Jan 1;441(1):23-37. (REVIEW)
PMID 22168437
 
The clonal and mutational evolution spectrum of primary triple-negative breast cancers.
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PMID 22495314
 
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Written05-2012Daphne W Bell
National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health, Bethesda, MD, USA

Citation

This paper should be referenced as such :
Bell, DW
PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):876-883.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PIK3R1ID41717ch5q13.html

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