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

2012-05-01   Daphne W Bell 

National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health, Bethesda, MD, USA

Identity

HGNC
LOCATION
5q13.1
LOCUSID
ALIAS
AGM7,GRB1,IMD36,p85,p85-ALPHA
FUSION GENES

DNA/RNA

Atlas Image
(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.

Proteins

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).
Atlas Image
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).
Atlas Image
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 name
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 name
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 name
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 name
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 name
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 name
Urothelial cancer
Oncogenesis
Somatic mutations in PIK3R1 have been reported in 0.7% (1 of 145) of urothelial cancers (Sjodahl et al., 2011).
Entity name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
118422132002Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85alpha.Almind K et al
86282861996Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain.Antonetti DA et al
96048781998Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha): preliminary evidence indicates a potential role of this variant in the acute insulin response and type 2 diabetes in Pima women.Baier LJ et al
218170132011Mutations in CIC and FUBP1 contribute to human oligodendroglioma.Bettegowda C et al
194075562009Expression status and mutational analysis of the PTEN and P13K subunit genes in ovarian granulosa cell tumors.Bittinger S et al
157136202005Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice.Brachmann SM et al
217203652011Integrated genomic analyses of ovarian carcinoma.
202121132010Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase.Chagpar RB et al
205707292010Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking.Chamberlain MD et al
146731652004p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity.Chen D et al
219849762011High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability.Cheung LW et al
223423442012p85α SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation.Comb WC et al
223519332012Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.Conley ME et al
83138961994PI 3-kinase: structural and functional analysis of intersubunit interactions.Dhand R et al
171321022006Mutations in the inter-SH2 domain of the regulatory subunit of phosphoinositide 3-kinase: effects on catalytic subunit binding and holoenzyme function.Elis W et al
199067272010COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer.Forbes SA et al
155420632004The iSH2 domain of PI 3-kinase is a rigid tether for p110 and not a conformational switch.Fu Z et al
174707922007Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers.Geering B et al
105254021999Crystal structure of the C-terminal SH2 domain of the p85alpha regulatory subunit of phosphoinositide 3-kinase: an SH2 domain mimicking its own substrate.Hoedemaeker FJ et al
180793942007The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.Huang CH et al
86213821996A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK Is generated by alternative splicing of the p85alpha gene.Inukai K et al
90654541997p85alpha gene generates three isoforms of regulatory subunit for phosphatidylinositol 3-kinase (PI 3-Kinase), p50alpha, p55alpha, and p85alpha, with different PI 3-kinase activity elevating responses to insulin.Inukai K et al
199626652009Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation.Jaiswal BS et al
223023502012Somatic mutations in the Notch, NF-KB, PIK3CA, and Hedgehog pathways in human breast cancers.Jiao X et al
187723972008Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.Jones S et al
206684512010Diverse somatic mutation patterns and pathway alterations in human cancers.Kan Z et al
146557562003Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas.Knobbe CB et al
218251342011Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85alpha Src homology-2 domains.Lee JY et al
182455212008Association between phosphatidylinositol 3-kinase regulatory subunit p85alpha Met326Ile genetic polymorphism and colon cancer risk.Li L et al
86486291996Crystal structure of P13K SH3 domain at 20 angstroms resolution.Liang J et al
223276222012Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.Lipson D et al
117813592002Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes.Mauvais-Jarvis F et al
221684372012Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking.Mellor P et al
176268832007Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.Miled N et al
156059842004Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas.Mizoguchi M et al
89620581996Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit.Musacchio A et al
85997631996Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes.Nolte RT et al
196340592010Somatic mutation of PIK3R1 gene is rare in common human cancers.Park SW et al
203489262010The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation.Park SW et al
211639642011The genetic landscape of the childhood cancer medulloblastoma.Parsons DW et al
116063752001The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors.Philp AJ et al
224953142012The clonal and mutational evolution spectrum of primary triple-negative breast cancers.Shah SP et al
168486812006Mutation of the PI3' kinase gene in a human colon carcinoma cell line, HCC2998.Shi BH et al
169599742006The consensus coding sequences of human breast and colorectal cancers.Sjöblom T et al
215331742011A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1.Sjödahl G et al
207137022010Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.Sun M et al
205306652010The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling.Taniguchi CM et al
214782952011PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer.Urick ME et al
203792072010The emerging mechanisms of isoform-specific PI3K signalling.Vanhaesebroeck B et al
203489232010A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response.Winnay JN et al
199151462009Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants.Wu H et al

Other Information

Locus ID:

NCBI: 5295
MIM: 171833
HGNC: 8979
Ensembl: ENSG00000145675

Variants:

dbSNP: 5295
ClinVar: 5295
TCGA: ENSG00000145675
COSMIC: PIK3R1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000145675ENST00000320694P27986
ENSG00000145675ENST00000336483P27986
ENSG00000145675ENST00000517698E5RK66
ENSG00000145675ENST00000519025H0YBC2
ENSG00000145675ENST00000520675H0YB27
ENSG00000145675ENST00000521381P27986
ENSG00000145675ENST00000521381A0A2X0SFG1
ENSG00000145675ENST00000521409E5RJY0
ENSG00000145675ENST00000521657P27986
ENSG00000145675ENST00000521657A0A2X0SFG1
ENSG00000145675ENST00000522084E5RHI0
ENSG00000145675ENST00000523807E5RGI8
ENSG00000145675ENST00000523872P27986

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
ErbB signaling pathwayKEGGko04012
Phosphatidylinositol signaling systemKEGGko04070
Autophagy - animalKEGGko04140
mTOR signaling pathwayKEGGko04150
ApoptosisKEGGko04210
Axon guidanceKEGGko04360
VEGF signaling pathwayKEGGko04370
Focal adhesionKEGGko04510
Toll-like receptor signaling pathwayKEGGko04620
Jak-STAT signaling pathwayKEGGko04630
Natural killer cell mediated cytotoxicityKEGGko04650
T cell receptor signaling pathwayKEGGko04660
B cell receptor signaling pathwayKEGGko04662
Fc epsilon RI signaling pathwayKEGGko04664
Leukocyte transendothelial migrationKEGGko04670
Regulation of actin cytoskeletonKEGGko04810
Insulin signaling pathwayKEGGko04910
Progesterone-mediated oocyte maturationKEGGko04914
Type II diabetes mellitusKEGGko04930
Colorectal cancerKEGGko05210
Renal cell carcinomaKEGGko05211
Pancreatic cancerKEGGko05212
Endometrial cancerKEGGko05213
GliomaKEGGko05214
Prostate cancerKEGGko05215
MelanomaKEGGko05218
Chronic myeloid leukemiaKEGGko05220
Acute myeloid leukemiaKEGGko05221
Small cell lung cancerKEGGko05222
Non-small cell lung cancerKEGGko05223
ErbB signaling pathwayKEGGhsa04012
Phosphatidylinositol signaling systemKEGGhsa04070
Autophagy - animalKEGGhsa04140
mTOR signaling pathwayKEGGhsa04150
ApoptosisKEGGhsa04210
Axon guidanceKEGGhsa04360
VEGF signaling pathwayKEGGhsa04370
Focal adhesionKEGGhsa04510
Toll-like receptor signaling pathwayKEGGhsa04620
Jak-STAT signaling pathwayKEGGhsa04630
Natural killer cell mediated cytotoxicityKEGGhsa04650
T cell receptor signaling pathwayKEGGhsa04660
B cell receptor signaling pathwayKEGGhsa04662
Fc epsilon RI signaling pathwayKEGGhsa04664
Leukocyte transendothelial migrationKEGGhsa04670
Regulation of actin cytoskeletonKEGGhsa04810
Insulin signaling pathwayKEGGhsa04910
Type II diabetes mellitusKEGGhsa04930
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Renal cell carcinomaKEGGhsa05211
Pancreatic cancerKEGGhsa05212
Endometrial cancerKEGGhsa05213
GliomaKEGGhsa05214
Prostate cancerKEGGhsa05215
MelanomaKEGGhsa05218
Chronic myeloid leukemiaKEGGhsa05220
Acute myeloid leukemiaKEGGhsa05221
Small cell lung cancerKEGGhsa05222
Non-small cell lung cancerKEGGhsa05223
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Progesterone-mediated oocyte maturationKEGGhsa04914
Aldosterone-regulated sodium reabsorptionKEGGko04960
Aldosterone-regulated sodium reabsorptionKEGGhsa04960
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
AmoebiasisKEGGko05146
AmoebiasisKEGGhsa05146
Carbohydrate digestion and absorptionKEGGko04973
Carbohydrate digestion and absorptionKEGGhsa04973
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Cholinergic synapseKEGGhsa04725
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
HIF-1 signaling pathwayKEGGhsa04066
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
FoxO signaling pathwayKEGGhsa04068
Thyroid hormone signaling pathwayKEGGhsa04919
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
Platelet activationKEGGhsa04611
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Central carbon metabolism in cancerKEGGhsa05230
Choline metabolism in cancerKEGGhsa05231
Central carbon metabolism in cancerKEGGko05230
Choline metabolism in cancerKEGGko05231
PI3K-Akt signalingKEGGhsa_M00676
PI3K-Akt signalingKEGGM00676
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Regulation of lipolysis in adipocytesKEGGhsa04923
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by EGFR in CancerREACTOMER-HSA-1643713
Signaling by Ligand-Responsive EGFR Variants in CancerREACTOMER-HSA-5637815
Constitutive Signaling by Ligand-Responsive EGFR Cancer VariantsREACTOMER-HSA-1236382
Signaling by EGFRvIII in CancerREACTOMER-HSA-5637812
Constitutive Signaling by EGFRvIIIREACTOMER-HSA-5637810
Signaling by FGFR in diseaseREACTOMER-HSA-1226099
Signaling by FGFR1 in diseaseREACTOMER-HSA-5655302
FGFR1 mutant receptor activationREACTOMER-HSA-1839124
Signaling by cytosolic FGFR1 fusion mutantsREACTOMER-HSA-1839117
Signaling by FGFR2 in diseaseREACTOMER-HSA-5655253
Signaling by FGFR3 in diseaseREACTOMER-HSA-5655332
Signaling by FGFR4 in diseaseREACTOMER-HSA-5655291
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
TCR signalingREACTOMER-HSA-202403
Downstream TCR signalingREACTOMER-HSA-202424
Costimulation by the CD28 familyREACTOMER-HSA-388841
CD28 co-stimulationREACTOMER-HSA-389356
CD28 dependent PI3K/Akt signalingREACTOMER-HSA-389357
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Antigen activates B Cell Receptor (BCR) leading to generation of second messengersREACTOMER-HSA-983695
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Role of phospholipids in phagocytosisREACTOMER-HSA-2029485
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Regulation of signaling by CBLREACTOMER-HSA-912631
Interleukin-7 signalingREACTOMER-HSA-1266695
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GP1b-IX-V activation signallingREACTOMER-HSA-430116
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Cell surface interactions at the vascular wallREACTOMER-HSA-202733
Tie2 SignalingREACTOMER-HSA-210993
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by FGFRREACTOMER-HSA-190236
Signaling by FGFR1REACTOMER-HSA-5654736
Downstream signaling of activated FGFR1REACTOMER-HSA-5654687
PI-3K cascade:FGFR1REACTOMER-HSA-5654689
Signaling by FGFR2REACTOMER-HSA-5654738
Downstream signaling of activated FGFR2REACTOMER-HSA-5654696
PI-3K cascade:FGFR2REACTOMER-HSA-5654695
Signaling by FGFR3REACTOMER-HSA-5654741
Downstream signaling of activated FGFR3REACTOMER-HSA-5654708
PI-3K cascade:FGFR3REACTOMER-HSA-5654710
Signaling by FGFR4REACTOMER-HSA-5654743
Downstream signaling of activated FGFR4REACTOMER-HSA-5654716
PI-3K cascade:FGFR4REACTOMER-HSA-5654720
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by ERBB2REACTOMER-HSA-1227986
PI3K events in ERBB2 signalingREACTOMER-HSA-1963642
Signaling by ERBB4REACTOMER-HSA-1236394
PI3K events in ERBB4 signalingREACTOMER-HSA-1250342
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (q) signalling eventsREACTOMER-HSA-416476
G alpha (12/13) signalling eventsREACTOMER-HSA-416482
G-protein beta:gamma signallingREACTOMER-HSA-397795
G beta:gamma signalling through PI3KgammaREACTOMER-HSA-392451
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
PI MetabolismREACTOMER-HSA-1483255
Synthesis of PIPs at the plasma membraneREACTOMER-HSA-1660499
Cell-Cell communicationREACTOMER-HSA-1500931
Nephrin interactionsREACTOMER-HSA-373753
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Insulin resistanceKEGGhsa04931
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
Signaling by FGFR3 point mutants in cancerREACTOMER-HSA-8853338
Signaling by FGFR3 fusions in cancerREACTOMER-HSA-8853334
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
Platinum drug resistanceKEGGko01524
Endocrine resistanceKEGGko01522
Platinum drug resistanceKEGGhsa01524
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Endocrine resistanceKEGGhsa01522
RET signalingREACTOMER-HSA-8853659
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224
Signaling by METREACTOMER-HSA-6806834
MET activates PI3K/AKT signalingREACTOMER-HSA-8851907
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164746311everolimusChemicalClinicalAnnotationassociatedPD
PA24684AKT1GenePathwayassociated28362716
PA27844ERBB2GenePathwayassociated
PA27846ERBB3GenePathwayassociated
PA27847ERBB4GenePathwayassociated
PA28180FLT1GenePathwayassociated28362716
PA28183FLT4GenePathwayassociated28362716
PA30086KDRGenePathwayassociated28362716
PA33308PIK3CAGeneMultilinkAnnotationassociated26807692
PA33942PTENGeneMultilinkAnnotationassociated26807692
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD
PA444522HyperglycemiaDiseaseClinicalAnnotationassociatedPD
PA444773LeukopeniaDiseaseClinicalAnnotationassociatedPD
PA445062NeoplasmsDiseaseMultilinkAnnotationassociated26807692
PA7360EGFRGenePathwayassociated

References

Pubmed IDYearTitleCitations
180793942007The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.186
219849762011High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability.173
21740511990Purification and characterization of phosphoinositide 3-kinase from rat liver.148
199626652009Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation.134
183284272008Yes and PI3K bind CD95 to signal invasion of glioblastoma.110
147698562004Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells.101
182272182008PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation.97
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
202121132010Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase.82
235692372013Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells.74

Citation

Daphne W Bell

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

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/41717/pik3r1