Alternative titles; symbols
HGNC Approved Gene Symbol: PPP2R1B
Cytogenetic location: 11q23.1 Genomic coordinates (GRCh38): 11:111,688,000-111,766,389 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.1 | Lung cancer, somatic | 211980 | 3 |
Serine/threonine protein phosphatase-2A (PP2A) is an important regulatory enzyme that downregulates the mitogen-activated protein kinase (MAPK) cascade (see 176948), relays signals for cell proliferation, and may be linked to carcinogenesis. The PP2A holoenzyme exists in several trimeric forms consisting of a 36-kD core catalytic subunit (PP2AC; see 176915), a 65-kD structural/regulatory component (PP2AA), and a variable regulatory subunit (PP2AB; see 604941) that confers distinct properties on the holoenzyme. Each subunit exists as multiple isoforms encoded by different genes, resulting in many forms of the PP2A trimer that differ in expression pattern and specificity. PPP2R1B encodes the beta isoform of the structural-regulatory A subunit, or PP2AA-beta. This subunit is necessary for interaction of the catalytic PP2AC and variable PP2AB subunits and is critical for phosphatase activity (Walter and Mumby, 1993; Wang et al., 1998).
Loss of heterozygosity (LOH) at chromosome 11q22-q24 has been associated with lung, colon, breast, cervical, head and neck, and ovarian cancers, as well as melanoma (Arai et al., 1996). Introduction of a normal chromosome 11, or a derivative t(X;11) chromosome containing 11pter-q23, can reverse the tumorigenic potential of several types of cancer cells and Wilms tumor when introduced into nude mice. These studies suggest that 1 or more tumor suppressor genes are located centromeric to the t(X;11) breakpoint at chromosome 11q23. Because of a high frequency of LOH in lung cancer cells involving D11S1647 and D11S1987, Wang et al. (1998) systematically surveyed the region between these 2 markers for candidate tumor suppressor genes. Over 100 candidate genes and ESTs were identified from a radiation hybrid map of chromosome 11 and from the NCBI transcript map, including an EST corresponding to PPP2R1B.
Baysal et al. (1998) determined that the PPP2R1B gene contains 15 exons and spans approximately 27 kb.
Wang et al. (1998) determined the precise physical location of the PPP2R1B gene by colocalizing it within P1-derived artificial chromosome (PAC) clones containing sequence tagged sites on chromosome 11q22-q23. They confirmed that the PPP2R1B gene is located in a region showing high frequency LOH.
Sablina et al. (2007) found that suppression of PP2A A-beta expression allowed immortalized human cell lines to achieve a tumorigenic state. Cancer-associated A-beta mutants failed to reverse this tumorigenic phenotype, indicating that the mutants functioned as null alleles. Cancer-derived A-beta mutants failed to form a complex with the small GTPase RALA (179550), whereas wildtype A-beta-containing complexes dephosphorylated RALA at ser183 and ser194, inactivating RALA and abolishing its transforming function. Sablina et al. (2007) concluded that PP2A A-beta is a tumor suppressor that transforms immortalized cells by regulating RALA function.
Wang et al. (1998) identified somatic alterations in the PPP2R1B gene in 15% (5 in 32) of primary lung tumors, 6% (4 in 70) of lung tumor-derived cell lines, and 15% (2 in 13) of primary colon tumors. One deletion mutation generated a truncated PP2A-A-beta protein that was unable to bind to the catalytic subunit of the PP2A holoenzyme. The authors suggested that the PPP2R1B gene product may suppress tumor development through its role in cell cycle regulation and cellular growth control.
Deletion of 11q23 is a common alteration in parathyroid adenomas and hyperplasias. To evaluate the role of the PPP2R1B gene in the pathogenesis of parathyroid lesions, Hemmer et al. (2002) performed PCR-based SSCP and direct sequencing on 6 parathyroid hyperplasias and 12 adenomas. The gly90-to-asp mutation (603113.0001) was detected in 1 adenoma; the common gly allele and the variant asp allele were detected by direct sequencing in the patient's somatic cells. Hemmer et al. (2002) concluded that mutations of PPP2R1B are not frequent in parathyroid lesions, and that other genes located at 11q23 may be more closely associated with the pathogenesis of parathyroid hyperplasia and adenoma.
The alterations observed by Wang et al. (1998) in the PPP2R1B gene in tumor-derived cell lines and primary tumors included deletions, frameshifts, and point mutations leading to nonconservative amino acid substitutions. In a lung cancer cell line 1 allele was found to carry a G-to-A transition of nucleotide 298, which resulted in a change of the conserved glycine-90 to aspartic acid (G90D). The G90D alteration was found in 2 separate tumors and not in surrounding normal tissue, which suggested that this site may be a hotspot for mutation.
Hemmer et al. (2002) found the G90D mutation in 1 of 12 parathyroid adenomas. Somatic cells showed the presence of both the gly allele and the variant asp allele.
Arai, Y., Hosoda, F., Nakayama, K., Ohki, M. A yeast artificial chromosome contig and NotI restriction map that spans the tumor suppressor gene(s) locus, 11q.22.2-q23.3. Genomics 35: 196-206, 1996. [PubMed: 8661121] [Full Text: https://doi.org/10.1006/geno.1996.0339]
Baysal, B. E., Farr, J. E., Goss, J. R., Devlin, B., Richard, C. W., III. Genomic organization and precise physical location of protein phosphatase 2A regulatory subunit A beta isoform gene on chromosome band 11q23. Gene 217: 107-116, 1998. [PubMed: 9795170] [Full Text: https://doi.org/10.1016/s0378-1119(98)00350-3]
Hemmer, S., Wasenius, V.-M., Haglund, C., Zhu, Y., Knuutila, S., Franssila, K., Joensuu, H. Alterations in the suppressor gene PPP2R1B in parathyroid hyperplasias and adenomas. Cancer Genet. Cytogenet. 134: 13-17, 2002. [PubMed: 11996789] [Full Text: https://doi.org/10.1016/s0165-4608(01)00597-0]
Sablina, A. A., Chen, W., Arroyo, J. D., Corral, L., Hector, M., Bulmer, S. E., DeCaprio, J. A., Hahn, W. C. The tumor suppressor PP2A A-beta regulates the RalA GTPase. Cell 129: 969-982, 2007. [PubMed: 17540176] [Full Text: https://doi.org/10.1016/j.cell.2007.03.047]
Walter, G., Mumby, M. Protein serine/threonine phosphatases and cell transformation. Biochim. Biophys. Acta 1155: 207-226, 1993. [PubMed: 8395218] [Full Text: https://doi.org/10.1016/0304-419x(93)90005-w]
Wang, S. S., Esplin, E. D., Li, J. L., Huang, L., Gazdar, A., Minna, J., Evans, G. A. Alterations of the PPP2R1B gene in human lung and colon cancer. Science 282: 284-287, 1998. [PubMed: 9765152] [Full Text: https://doi.org/10.1126/science.282.5387.284]