| Written | 2012-05 | Daphne W Bell |
| National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health, Bethesda, MD, USA |
| Identity |
| Alias_names | phosphoinositide-3-kinase, regulatory subunit 1 (alpha) |
| Alias_symbol (synonym) | GRB1 |
| p85-ALPHA | |
| p85 | |
| Other alias | |
| HGNC (Hugo) | PIK3R1 |
| LocusID (NCBI) | 5295 |
| Atlas_Id | 41717 |
| Location | 5q13.1 [Link to chromosome band 5q13] |
| Location_base_pair | Starts at 68288424 and ends at 68301821 bp from pter ( according to hg19-Feb_2009) [Mapping PIK3R1.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| LRCH1 (13q14.13) / PIK3R1 (5q13.1) | NFIA (1p31.3) / PIK3R1 (5q13.1) | PIK3R1 (5q13.1) / KANK1 (9p24.3) | |
| PIK3R1 (5q13.1) / NDUFB7 (19p13.12) | PIK3R1 (5q13.1) / PIK3R1 (5q13.1) |
| 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 |
| Note | |
| 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). |
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| 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 journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/PIK3R1ID41717ch5q13.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ] |
| Solid Tumors | TT_t0509q13p24ID106833 | TT_t0519q13p13ID106567 |
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