Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PIK3R2
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38) : 19:18,153,163-18,170,532 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.11 | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 | 603387 | Autosomal dominant | 3 |
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates the inositol ring of phosphatidylinositol and related compounds at the 3-prime position. The products of these reactions are thought to serve as second messengers in growth signaling pathways. The kinase itself is made up of a catalytic subunit of molecular mass 110 kD (p110; e.g., PIK3CA, 171834) and a regulatory subunit of molecular mass 85, 55, or 50 kD (summary by Hoyle et al., 1994; Janssen et al., 1998).
Otsu et al. (1991) showed that the bovine PI3K p85 subunit consists of 2 closely related proteins, p85-alpha (171833) and p85-beta. They cloned cDNAs encoding both p85 subunits, each of which is 724 amino acids long. The subunits share 62% amino acid identity across their entire length. Both sequences contain an N-terminal SH3 region, 2 SH2 regions, and a region of homology to BCR (151410).
Janssen et al. (1998) determined the human p85-beta cDNA sequence.
Functional expression studies by Otsu et al. (1991) showed that both bovine p85 subunits bound tyrosine kinase receptors.
Hale et al. (2006) generated a laryngeal carcinoma cell line constitutively expressing influenza A virus NS1 protein and found that NS1 bound specifically to p85-beta. The NS1 protein from various influenza strains also bound p85-beta, but not p85-alpha. Expression of NS1 led to induction of PI3K signaling, including phosphorylation of AKT (164730) at ser473. Binding of p85-beta and activation of PI3K required tyr89 of NS1, and mutant viruses expressing NS1 with a tyr89-to-phe substitution grew more slowly in cell culture than wildtype viruses. Hale et al. (2006) proposed that activation of PI3K signaling in influenza A virus-infected cells is important for efficient virus replication.
Using mouse embryonic fibroblasts, Park et al. (2010) showed that, in addition to regulating PI3K function, p85-alpha and p85-beta regulated the function of Xbp1s (XBP1; 194355), a transcription factor that orchestrates the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress. Both p85-alpha and p85-beta bound Xbp1s and increased its nuclear translocation, and it appeared that the p110 PI3K catalytic subunit and Xbp1s competed for binding of these regulatory subunits. p85-alpha and p85-beta formed an inactive dimer that was disrupted by insulin in a time-dependent manner, which promoted their association with Xbp1s. Refeeding of wildtype mice after fasting induced ER stress that was quickly resolved, as measured by Xbp1s levels. In contrast, obese and insulin-resistant ob/ob (LEP; 164160) mice could not resolve the ER stress induced during refeeding, and nuclear translocation of Xbp1s was absent in ob/ob mice. Overexpression of p85-alpha or p85-beta in livers of ob/ob mice increased glucose tolerance and reduced blood glucose concentrations.
To assess the impact of the AKT3 (611223), PIK3R2, and PIK3CA mutations in individuals with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and megalencephaly polymicrogyria-polydactyly hydrocephalus syndrome-1 (MPPH1; 603387) on PI3K activity, Riviere et al. (2012) used immunostaining to compare PIP3 amounts in lymphoblastoid cell lines derived from 4 mutation carriers with megalencephaly to those in control and PTEN (601728)-mutant cells. Consistent with elevated PI3K activity, and similar to what is seen with PTEN loss, all 3 lines with PIK3R2 or PIK3CA mutations showed significantly more PIP3 staining than control cells, as well as greater localization of active phosphoinositide-dependent kinase-1 (PDPK1; 605213) to the cell membrane. Treatment with the PI3K inhibitor PI-103 resulted in less PIP3 in the PIK3R2 G373R (603157.0001) and PIK3CA E453del (171834.0014) mutant lines, confirming that these results are PI3K-dependent. Riviere et al. (2012) found no evidence for increased PI3K activity in the AKT3-mutant line, consistent with a mutation affecting a downstream effector of PI3K. Protein blot analysis showed higher amounts of phosphorylated S6 protein and 4E-BP1 in all mutant cell lines compared to controls. Although PI-103 treatment reduced S6 phosphorylation in control and mutant lines, the latter showed relative resistance to PI3K inhibition, consistent with elevated signaling through the pathway. Riviere et al. (2012) concluded that the megalencephaly-associated mutations result in higher PI3K activity and PI3K-mTOR signaling.
Volinia et al. (1992) used in situ hybridization to map the PIK3R2 gene to human chromosome 19q13.2-q13.4.
Janssen et al. (1998) analyzed DNA from a patient with chronic myeloproliferative disorder. They identified an oncogenic fusion of the 5-prime end of p85-beta and the 3-prime end of HUMORF8 (USP8; 603158).
Riviere et al. (2012) performed exome sequencing in the oldest of 3 affected sibs with MPPH1 and identified a heterozygous mutation in the PIK3R2 gene (G373R; 603157.0001). Sanger sequencing confirmed the presence of the mutation in all 3 affected sibs and its absence in the saliva and blood of both parents and the unaffected sister, showing germline mosaicism in 1 parent. Sequencing of the PIK3R2 gene in 40 individuals with megalencephaly identified the same nucleotide change in 10 additional subjects with MPPH, and this mutation was shown to be de novo in all subjects for whom parental DNA was available. The mutation occurred at a CpG dinucleotide, which might explain its recurrence.
Oak et al. (2006) crossed mice with a floxed Pik3r1 allele and a null Pik3r2 allele with Lck (153390)-Cre transgenic mice to generate a strain in which class IA Pi3k expression and function were essentially abrogated in T cells beginning at the double-negative stage. Histopathologic analysis of these mice showed development of organ-specific autoimmunity resembling Sjogren syndrome (SS; 270150). By 3 to 8 months of age, mutant mice developed corneal opacity and eye lesions due to irritation and constant scratching. Mutant mice showed marked lymphocytic infiltration of lacrimal glands and serum antinuclear and anti-Ssa (SSA1; 109092) antibodies, but no kidney pathology. Cd4-positive T cells, which were the predominant infiltrating cells in lacrimal glands of mutant mice, exhibited aberrant differentiation in vitro. Oak et al. (2006) concluded that impaired class IA PI3K signaling in T cells can lead to organ-specific autoimmunity, and they proposed that class IA Pi3k-deficient mice manifest the cardinal features of human primary SS.
In 13 individuals with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-1 (MPPH1; 603387) from 11 unrelated families, Riviere et al. (2012) identified a heterozygous 1117G-A transition in the PIK3R2 gene, resulting in a gly373-to-arg (G373R) substitution in the PIK3R2 gene. This mutation was shown to be de novo in all subjects for whom parental DNA was available. The mutation occurred at a CpG dinucleotide, which might explain its recurrence.
In an 8-year-old Japanese girl with MPPH1 (603387), Nakamura et al. (2014) identified a de novo heterozygous c.1202T-C transition in the PIK3R2 gene, resulting in a leu401-to-pro (L401P) substitution in the SH2 domain. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project database or in 144 in-house control exomes. Functional studies of the variant were not performed. The patient had previously been reported by Tohyama et al. (2007).
Hale, B. G., Jackson, D., Chen, Y.-H., Lamb, R. A., Randall, R. E. Influenza A virus NS1 protein binds p85-beta and activates phosphatidylinositol-3-kinase signaling. Proc. Nat. Acad. Sci. 103: 14194-14199, 2006. [PubMed: 16963558] [Full Text: https://doi.org/10.1073/pnas.0606109103]
Hoyle, J., Yulug, I. G., Egan, S. E., Fisher, E. M. C. The gene that encodes the phosphatidylinositol-3 kinase regulatory subunit (p85-alpha) maps to chromosome 13 in the mouse. Genomics 24: 400-402, 1994. [PubMed: 7698770] [Full Text: https://doi.org/10.1006/geno.1994.1638]
Janssen, J. W. G., Schleithoff, L., Bartram, C. R., Schulz, A. S. An oncogenic fusion product of the phosphatidylinositol 3-kinase p85-beta subunit and HUMORF8, a putative deubiquitinating enzyme. Oncogene 16: 1767-1772, 1998. [PubMed: 9582025] [Full Text: https://doi.org/10.1038/sj.onc.1201695]
Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Matsumoto, N., Saitsu, H. AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. (Letter) Clin. Genet. 85: 396-298, 2014. [PubMed: 23745724] [Full Text: https://doi.org/10.1111/cge.12188]
Oak, J. S., Deane, J. A., Kharas, M. G., Luo, J., Lane, T. E., Cantley, L. C., Fruman, D. A. Sjogren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase. Proc. Nat. Acad. Sci. 103: 16882-16887, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 106: 10871 only, 2009. [PubMed: 17071741] [Full Text: https://doi.org/10.1073/pnas.0607984103]
Otsu, M., Hiles, I., Gout, I., Fry, M. J., Ruiz-Larrea, F., Panayotou, G., Thompson, A., Dhand, R., Hsuan, J., Totty, N., Smith, A. D., Morgan, S. J., Courtneidge, S. A., Parker, P. J., Waterfield, M. D. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60(c-src) complexes, and PI3-kinase. Cell 65: 91-104, 1991. [PubMed: 1707345] [Full Text: https://doi.org/10.1016/0092-8674(91)90411-q]
Park, S. W., Zhou, Y., Lee, J., Lu, A., Sun, C., Chung, J., Ueki, K., Ozcan, U. The regulatory subunits of PI3K, p85-alpha and p85-beta, interact with XBP-1 and increase its nuclear translocation. Nature Med. 16: 429-437, 2010. [PubMed: 20348926] [Full Text: https://doi.org/10.1038/nm.2099]
Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genet. 44: 934-940, 2012. [PubMed: 22729224] [Full Text: https://doi.org/10.1038/ng.2331]
Tohyama, J., Akasaka, N., Saito, N., Yoshimura, J., Nishiyama, K., Kato, M. Megalencephaly and polymicrogyria with polydactyly syndrome. Pediat. Neurol. 37: 148-151, 2007. [PubMed: 17675034] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2007.04.008]
Volinia, S., Patracchini, P., Otsu, M., Hiles, I., Gout, I., Calzolari, E., Bernardi, F., Rooke, L., Waterfield, M. D. Chromosomal localization of human p85-alpha, a subunit of phosphatidylinositol 3-kinase, and its homologue p85-beta. Oncogene 7: 789-793, 1992. [PubMed: 1314371]