Alternative titles; symbols
HGNC Approved Gene Symbol: PIK3CB
Cytogenetic location: 3q22.3 Genomic coordinates (GRCh38): 3:138,652,698-138,834,928 (from NCBI)
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. They have been implicated as participants in signaling pathways regulating cell growth by virtue of their activation in response to various mitogenic stimuli. PI3Ks are composed of a 110-kD catalytic subunit, such as PIK3CB, and an 85-kD adaptor subunit (Hu et al., 1993).
To identify human genes encoding the PI3K catalytic subunit, Hu et al. (1993) carried out RT-PCR with RNA from a T-lymphocyte cell line and degenerate primers based on regions conserved between a bovine and a yeast PI3K. The authors recovered a partial cDNA encoding a human PI3K and used it to isolate additional cDNAs from an embryonic kidney cell line (293) library. The predicted 1,070-amino acid protein, called p110-beta by them, is 42% identical to that of bovine p110. Northern blot analysis revealed that the major 4.8-kb p110-beta transcript was expressed in several human and rodent cell lines, as well as in all mouse tissues tested. Minor larger transcripts were detected in some tissues and cell lines.
Using 293 cells expressing epitope tagged p110-beta, Hu et al. (1993) demonstrated that the protein has PI3K activity. Antibodies against p110-beta immunoprecipitated an endogenous PI3K activity from 293 cell lysates. Both the epitope-tagged protein and endogenous p110-beta associated with the 85-kD subunit in vivo.
Using flow-based adhesion assays with mouse and human platelets, Jackson et al. (2005) determined that p110-beta has a role in regulating the formation and stability of alpha-2B (ITGA2B; 607759)-beta-3 (ITGB3; 173470) integrin adhesion bonds, which are necessary for shear force-induced platelet activation. p100-beta sustained alpha-2B-beta-3 integrin activation and stabilized platelet aggregation by regulating both integrin-dependent calcium flux and Gi (see GNAI1; 139310) activation of RAP1B (179530).
Kossila et al. (2000) determined that the PIK3CB gene contains 22 exons that are 51 to 252 basepairs in length.
The International Radiation Hybrid Mapping Consortium mapped the PIK3CB gene to chromosome 3 (WI-14619).
Downregulation of the IGF1 (147440) pathway or IGF1 plasma levels is associated with an increased life span. Bonafe et al. (2003) tested the hypothesis that polymorphic variants of genes in the IGF1 response pathway, namely IGF1R (147370) (G/A, codon 1013), PI3KCB (T/C, -359 bp; A/G, -303 bp), IRS1 (147545) (G/A, codon 972), and FOXO1A (136533) (T/C, +97347 bp), play a role in systemic IGF1 regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF1R had low levels of free plasma IGF1 and were more represented among long-lived people. Moreover, genotype combinations at IGF1R and PIK3CB genes affect free IGF1 plasma levels and longevity. Genotype combinations of an A allele at the IGF1R locus and a T allele at the PI3CKB locus (A+/T+ subjects) affected IGF1 plasma levels (with A-/T- individuals having the highest free IGF1 plasma levels), as well as longevity, and the proportion of A+/T+ subjects significantly increased among long-lived individuals.
Liu et al. (2008) explored a wide-range genetic basis for the involvement of genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in anaplastic thyroid cancer (ATC) and follicular thyroid cancer (FTC; 188470). They found frequent copy gains of RTK genes including EGFR (131550), and VEGFR1 (165070), and PIK3CA (171834) and PIK3CB in the P13K/Akt pathway. Copy number gain of PIK3CB was found in 16 of 42 ATCs (38%) and 25 of 55 FTCs (46%). RTK gene copy gains were preferentially associated with phosphorylation of Akt, suggesting their dominant role in activating the P13K/Akt pathway. Liu et al. (2008) concluded that genetic alterations in the RTKs and P13K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.
Le Stunff et al. (2008) studied the p110-beta gene as a candidate gene for association with insulin resistance (IR) and fasting glycemia in severely obese children. They found that a SNP (rs361072) located in the promoter of the p110-beta gene was associated with fasting glucose (P = 0.0002), insulin (P = 2.6 x 10(-8)), and homeostasis model assessment insulin resistance index (P = 1 x 10(-9)) in severely obese children. The effect of rs361072 was marginal or not significant in nonobese children. Le Stunff et al. (2008) concluded that the C allele of rs361072 attenuates IR in superobese children.
To investigate distinct functions of p110-beta, Jia et al. (2008) constructed conditional knockout mice. Ablation of p110-beta in the livers of the resulting mice led to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt (164730), suggesting the involvement of a kinase-independent role of p110-beta in insulin metabolic action. Using established mouse embryonic fibroblasts, Jia et al. (2008) found that removal of p110-beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110-beta-null cells with a wildtype or kinase-dead allele of p110-beta demonstrated that p110-beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110-beta was required for G protein-coupled receptor signaling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumor formation induced by Pten (601728) loss, ablation of p110-beta, but not that of p110-alpha (171834), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Jia et al. (2008) concluded that, taken together, their findings demonstrated both kinase-dependent and kinase-independent functions for p110-beta.
Ciraolo et al. (2010) developed a line of mice expressing catalytically inactive Pic3cb. Homozygous mutant mice were born and reached adulthood, but while homozygous mutant females were fully fertile, homozygous mutant males were subfertile. Mutant testis was reduced in size compared with wildtype and immunohistochemical analysis revealed few spermatozoa and hypocellular seminiferous tubules. Plasma testosterone was normal, and FSH (see 136530) was elevated, suggesting primary gonadic failure in mutant mice. Spermatogenic stem cell populations were observed, but they were progressively lost, suggesting that inactivation of Pic3cb results in a defect in spermatogenesis at later developmental stages. Kit (164920)-positive cells were lost in adult mutant testis, and pharmacologic inhibition of wildtype Pic3cb confirmed that Pic3cb is downstream of Kit activation.
Bonafe, M., Barbieri, M., Marchegiani, F., Olivieri, F., Ragno, E., Giampieri, C., Mugianesi, E., Centurelli, M., Franceschi, C. and Paolisso, G. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. J. Clin. Endocr. Metab. 88: 3299-3304, 2003. [PubMed: 12843179] [Full Text: https://doi.org/10.1210/jc.2002-021810]
Ciraolo, E., Morello, F., Hobbs, R. M., Wolf, F., Marone, R., Iezzi, M., Lu, X., Mengozzi, G., Altruda, F., Sorba, G., Guan, K., Pandolfi, P. P., Wymann, M. P., Hirsch, E. Essential role of the p110-beta subunit of phosphoinositide 3-OH kinase in male fertility. Molec. Biol. Cell 21: 704-711, 2010. [PubMed: 20053680] [Full Text: https://doi.org/10.1091/mbc.e09-08-0744]
Hu, P., Mondino, A., Skolnik, E. Y., Schlessinger, J. Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85. Molec. Cell. Biol. 13: 7677-7688, 1993. [PubMed: 8246984] [Full Text: https://doi.org/10.1128/mcb.13.12.7677-7688.1993]
Jackson, S. P., Schoenwaelder, S. M., Goncalves, I., Nesbitt, W. S., Yap, C. L., Wright, C. E., Kenche, V., Anderson, K. E., Dopheide, S. M., Yuan, Y., Sturgeon, S. A., Prabaharan, H., and 14 others. PI 3-kinase p110-beta: a new target for antithrombotic therapy. Nature Med. 11: 507-514, 2005. [PubMed: 15834429] [Full Text: https://doi.org/10.1038/nm1232]
Jia, S., Liu, Z., Zhang, S., Liu, P., Zhang, L., Lee, S. H., Zhang, J., Signoretti, S., Loda, M., Roberts, T. M., Zhao, J. J. Essential roles of PI(3)K-p110-beta in cell growth, metabolism and tumorigenesis. Nature 454: 776-779, 2008. Note: Erratum: Nature 533: 278 only, 2016. [PubMed: 18594509] [Full Text: https://doi.org/10.1038/nature07091]
Kossila, M., Sinkovic, M., Karkkainen, P., Laukkanen, M. O., Miettinen, R., Rissanen, J., Kekalainen, P., Kuusisto, J., Yla-Herttuala, S., Laakso, M. Gene encoding the catalytic subunit p110-beta of human phosphatidylinositol 3-kinase: cloning, genomic structure, and screening for variants in patients with type 2 diabetes. Diabetes 49: 1740-1743, 2000. [PubMed: 11016459] [Full Text: https://doi.org/10.2337/diabetes.49.10.1740]
Le Stunff, C., Dechartres, A., Del Giudice, E. M., Froguel, P., Bougneres, P. A single-nucleotide polymorphism in the p110-beta gene promoter is associated with partial protection from insulin resistance in severely obese adolescents. J. Clin. Endocr. Metab. 93: 212-215, 2008. [PubMed: 17971428] [Full Text: https://doi.org/10.1210/jc.2007-1822]
Liu, Z., Hou, P., Ji, M., H., Studeman, K., Jensen, K, Vasko, V., El-Naggar, A. K., Xing, M. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J. Clin. Endocr. Metab. 93: 3106-3116, 2008. [PubMed: 18492751] [Full Text: https://doi.org/10.1210/jc.2008-0273]