| 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 |
| 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 68292568 and ends at 68301821 bp from pter ( according to hg19-Feb_2009) [Mapping PIK3R1.png] |
| Fusion genes (updated 2016) | 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). |
| Bibliography |
| Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85alpha. |
| Almind K, Delahaye L, Hansen T, Van Obberghen E, Pedersen O, Kahn CR. |
| Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2124-8. Epub 2002 Feb 12. |
| PMID 11842213 |
| Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. |
| Antonetti DA, Algenstaedt P, Kahn CR. |
| Mol Cell Biol. 1996 May;16(5):2195-203. |
| PMID 8628286 |
| Variant 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, Wiedrich C, Hanson RL, Bogardus C. |
| Diabetes. 1998 Jun;47(6):973-5. |
| PMID 9604878 |
| 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 |
| Expression status and mutational analysis of the PTEN and P13K subunit genes in ovarian granulosa cell tumors. |
| Bittinger S, Alexiadis M, Fuller PJ. |
| Int J Gynecol Cancer. 2009 Apr;19(3):339-42. |
| PMID 19407556 |
| Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. |
| Brachmann SM, Ueki K, Engelman JA, Kahn RC, Cantley LC. |
| Mol Cell Biol. 2005 Mar;25(5):1596-607. |
| PMID 15713620 |
| 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 |
| Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. |
| Chagpar RB, Links PH, Pastor MC, Furber LA, Hawrysh AD, Chamberlain MD, Anderson DH. |
| Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5471-6. Epub 2010 Mar 8. |
| PMID 20212113 |
| Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking. |
| Chamberlain MD, Oberg JC, Furber LA, Poland SF, Hawrysh AD, Knafelc SM, McBride HM, Anderson DH. |
| Cell Signal. 2010 Oct;22(10):1562-75. Epub 2010 Jun 4. |
| PMID 20570729 |
| p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. |
| Chen D, Mauvais-Jarvis F, Bluher M, Fisher SJ, Jozsi A, Goodyear LJ, Ueki K, Kahn CR. |
| Mol Cell Biol. 2004 Jan;24(1):320-9. |
| PMID 14673165 |
| 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 |
| 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 |
| PI 3-kinase: structural and functional analysis of intersubunit interactions. |
| Dhand R, Hara K, Hiles I, Bax B, Gout I, Panayotou G, Fry MJ, Yonezawa K, Kasuga M, Waterfield MD. |
| EMBO J. 1994 Feb 1;13(3):511-21. |
| PMID 8313896 |
| Mutations in the inter-SH2 domain of the regulatory subunit of phosphoinositide 3-kinase: effects on catalytic subunit binding and holoenzyme function. |
| Elis W, Lessmann E, Oelgeschlager M, Huber M. |
| Biol Chem. 2006 Dec;387(12):1567-73. |
| PMID 17132102 |
| COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer. |
| Forbes SA, Tang G, Bindal N, Bamford S, Dawson E, Cole C, Kok CY, Jia M, Ewing R, Menzies A, Teague JW, Stratton MR, Futreal PA. |
| Nucleic Acids Res. 2010 Jan;38(Database issue):D652-7. Epub 2009 Nov 11. |
| PMID 19906727 |
| The iSH2 domain of PI 3-kinase is a rigid tether for p110 and not a conformational switch. |
| Fu Z, Aronoff-Spencer E, Wu H, Gerfen GJ, Backer JM. |
| Arch Biochem Biophys. 2004 Dec 15;432(2):244-51. |
| PMID 15542063 |
| Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. |
| Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B. |
| Proc Natl Acad Sci U S A. 2007 May 8;104(19):7809-14. Epub 2007 Apr 30. |
| PMID 17470792 |
| Crystal 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, Siegal G, Roe SM, Driscoll PC, Abrahams JP. |
| J Mol Biol. 1999 Oct 1;292(4):763-70. |
| PMID 10525402 |
| 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. |
| Science. 2007 Dec 14;318(5857):1744-8. |
| PMID 18079394 |
| A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK Is generated by alternative splicing of the p85alpha gene. |
| Inukai K, Anai M, Van Breda E, Hosaka T, Katagiri H, Funaki M, Fukushima Y, Ogihara T, Yazaki Y, Kikuchi, Oka Y, Asano T. |
| J Biol Chem. 1996 Mar 8;271(10):5317-20. |
| PMID 8621382 |
| p85alpha 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, Funaki M, Ogihara T, Katagiri H, Kanda A, Anai M, Fukushima Y, Hosaka T, Suzuki M, Shin BC, Takata K, Yazaki Y, Kikuchi M, Oka Y, Asano T. |
| J Biol Chem. 1997 Mar 21;272(12):7873-82. |
| PMID 9065454 |
| Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. |
| Jaiswal BS, Janakiraman V, Kljavin NM, Chaudhuri S, Stern HM, Wang W, Kan Z, Dbouk HA, Peters BA, Waring P, Dela Vega T, Kenski DM, Bowman KK, Lorenzo M, Li H, Wu J, Modrusan Z, Stinson J, Eby M, Yue P, Kaminker JS, de Sauvage FJ, Backer JM, Seshagiri S. |
| Cancer Cell. 2009 Dec 8;16(6):463-74. |
| PMID 19962665 |
| 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 |
| Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. |
| Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. |
| Science. 2008 Sep 26;321(5897):1801-6. Epub 2008 Sep 4. |
| PMID 18772397 |
| Diverse somatic mutation patterns and pathway alterations in human cancers. |
| Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K, Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS, Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ, Faham M, Seshagiri S. |
| Nature. 2010 Aug 12;466(7308):869-73. Epub 2010 Jul 28. |
| PMID 20668451 |
| Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. |
| Knobbe CB, Reifenberger G. |
| Brain Pathol. 2003 Oct;13(4):507-18. |
| PMID 14655756 |
| 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 |
| 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 |
| Crystal structure of P13K SH3 domain at 20 angstroms resolution. |
| Liang J, Chen JK, Schreiber ST, Clardy J. |
| J Mol Biol. 1996 Apr 5;257(3):632-43. |
| PMID 8648629 |
| 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 |
| Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. |
| Mauvais-Jarvis F, Ueki K, Fruman DA, Hirshman MF, Sakamoto K, Goodyear LJ, Iannacone M, Accili D, Cantley LC, Kahn CR. |
| J Clin Invest. 2002 Jan;109(1):141-9. |
| PMID 11781359 |
| 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 |
| 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. |
| Science. 2007 Jul 13;317(5835):239-42. |
| PMID 17626883 |
| 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. |
| PMID 15605984 |
| Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit. |
| Musacchio A, Cantley LC, Harrison SC. |
| Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14373-8. |
| PMID 8962058 |
| Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. |
| Nolte RT, Eck MJ, Schlessinger J, Shoelson SE, Harrison SC. |
| Nat Struct Biol. 1996 Apr;3(4):364-74. |
| PMID 8599763 |
| Somatic mutation of PIK3R1 gene is rare in common human cancers. |
| Park SW, Kang MR, Eom HS, Han JY, Ahn CH, Kim SS, Lee SH, Yoo NJ. |
| Acta Oncol. 2010b;49(1):125-7. |
| PMID 19634059 |
| 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. |
| Nat Med. 2010a Apr;16(4):429-37. Epub 2010 Mar 28. |
| PMID 20348926 |
| 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 |
| The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. |
| Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, Thomas RJ, Phillips WA. |
| Cancer Res. 2001 Oct 15;61(20):7426-9. |
| PMID 11606375 |
| The clonal and mutational evolution spectrum of primary triple-negative breast cancers. |
| Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SW, Morin GB, Watson P, Gelmon K, Chia S, Chin SF, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T, Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S. |
| Nature. 2012 Apr 4;486(7403):395-9. doi: 10.1038/nature10933. |
| PMID 22495314 |
| Mutation of the PI3' kinase gene in a human colon carcinoma cell line, HCC2998. |
| Shi BH, Nashimoto T, Andoh R, Konishi H, Kobayashi M, Xu Q, Ihara S, Fukui Y. |
| DNA Cell Biol. 2006 Jul;25(7):399-405. |
| PMID 16848681 |
| The consensus coding sequences of human breast and colorectal cancers. |
| Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. |
| Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7. |
| PMID 16959974 |
| 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 |
| Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha. |
| Sun M, Hillmann P, Hofmann BT, Hart JR, Vogt PK. |
| Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15547-52. Epub 2010 Aug 16. |
| PMID 20713702 |
| The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling. |
| Taniguchi CM, Winnay J, Kondo T, Bronson RT, Guimaraes AR, Aleman JO, Luo J, Stephanopoulos G, Weissleder R, Cantley LC, Kahn CR. |
| Cancer Res. 2010 Jul 1;70(13):5305-15. Epub 2010 Jun 8. |
| PMID 20530665 |
| 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 |
| 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 |
| Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants. |
| Wu H, Shekar SC, Flinn RJ, El-Sibai M, Jaiswal BS, Sen KI, Janakiraman V, Seshagiri S, Gerfen GJ, Girvin ME, Backer JM. |
| Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20258-63. Epub 2009 Nov 13. |
| PMID 19915146 |
| 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 |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Sep 18 17:11:17 CEST 2017 |
For comments and suggestions or contributions, please contact us