Alternative titles; symbols
HGNC Approved Gene Symbol: PPP1R2
Cytogenetic location: 3q29 Genomic coordinates (GRCh38): 3:195,514,428-195,543,325 (from NCBI)
Huang and Glinsmann (1976) first described 2 small heat-stable proteins in rabbit skeletal muscle as inhibitors of protein phosphatase-1 (PP1), one of the major types of serine/threonine phosphatases in eukaryotic cells. These 2 proteins were called phosphatase inhibitor-1 (IPP1, or PPP1R1A; 613246) and inhibitor-2 (IPP2). IPP1 is a protein of 165 residues with a molecular mass of 18.6 kD. IPP1 is active only after phosphorylation on a threonine residue by cAMP-dependent protein kinase, while IPP2 does not require phosphorylation (Cohen et al., 1977).
Helps et al. (1994) cloned the complete coding region of human IPP2. IPP2 is a protein of 203 residues with a molecular mass of 22.8 kD. The polypeptide shares 92% sequence identity with the rabbit homolog.
Sakagami and Kondo (1995) cloned and sequenced the cDNA for rat IPP2 (I-2) from a brain cDNA library. The open reading frame of 617 bp encodes a predicted protein of 205 amino acids with a molecular mass of 23.1 kD. The deduced amino acid sequence shows 86.3% homology to rabbit skeletal muscle I-2. By in situ hybridization they demonstrated that gene expression was mainly confined to the gray matter, with highest levels in the hippocampal pyramidal cell layer and the dentate granule cell layer.
IPP2 can interact with the catalytic subunit of PP1 (176875) to form a heterodimer called PP1I. This complex has been identified in the cytosol of many mammalian tissues. Permana and Mott (1997) cited reports indicating that the isolated heterodimer is inactive but can be activated in vitro by the reversible phosphorylation of IPP2 by glycogen synthase kinase at threonine-72. IPP2 can also be phosphorylated on ser86, ser120, and ser121 in vivo, as well as by casein kinase II in vitro.
Permana and Mott (1997) noted that insulin stimulation of PP1 results in dephosphorylation and activation of glycogen synthase-1 (GYS1; 138570). Among the Pima Indians, who show a high frequency of noninsulin-dependent diabetes mellitus (NIDDM), PP1 activity in skeletal muscle is decreased in insulin-resistant as compared to insulin-sensitive individuals. The genetic structure of both GYS1 (Majer et al., 1996) and the predominant beta-isoform of PP1C (Prochazka et al., 1995) appeared to be normal in the Pima Indian population. Of the proteins that bind and regulate PP1C, IPP2 is particularly interesting as a candidate enzyme responsible for insulin resistance, because upon binding PP1C, it induces conformational change and activation of the catalytic subunit. An unusually large proportion of inactive conformational states of PP1C can result from abnormal IPP2 function, which, in turn, can be a consequence of mutations in the gene coding for IPP2, at the PPP1R2 locus. IPP2 reversibly inhibits and facilitates the proper conformation of free catalytic units of PP1.
Permana and Mott (1997) determined that the authentic PPP1R2 gene contains 6 exons.
Permana and Mott (1997) determined that the authentic PPP1R2 gene is located on chromosome 3q29. The mapping to 3q29 was achieved by in situ hybridization. They showed that the previously reported homolog of PPP1R2 on chromosome 5 (Sanseau et al., 1994) is an intronless pseudogene. Comparative sequencing of PPP1R2 exons and splice junctions revealed no mutations in insulin-resistant Pima Indians.
Pseudogenes
Sanseau et al. (1994) isolated and characterized human IPP2 cDNA clones and sequenced an apparent IPP2 gene located in the major histocompatibility complex on chromosome 6. Two transcripts of approximately 2 kb and 4 kb were detected in all tissues tested. Analysis of cDNA sequences showed that the longer transcripts were similar to the shorter ones but contained extended 3-prime ends. The human nucleotide sequence showed 94% identity to the rabbit IPP2 sequence and encoded a peptide of 205 amino acids. IPP2 sequences are highly conserved throughout vertebrates. Southern hybridization results were consistent with the existence of a family of related IPP2 sequences in the human genome. Most of these are likely to be pseudogenes, since all of the cDNA clones examined could have originated from a single gene. By fluorescence in situ hybridization, Sanseau et al. (1994) mapped IPP2 sequences to several different human chromosomes. They sequenced 1 gene located in the major histocompatibility complex on chromosome 6 that contained the entire coding region of IPP2. The location was given as 6p21.31 for this presumed pseudogene (PPP1R2P).
Cohen, P., Rylatt, D. B., Nimmo, G. A. The hormonal control of glycogen metabolism: the amino acid sequence at the phosphorylation site of protein phosphatase inhibitor-1. FEBS Lett. 76: 182-186, 1977. [PubMed: 193727] [Full Text: https://doi.org/10.1016/0014-5793(77)80147-6]
Helps, N. R., Street, A. J., Elledge, S. J., Cohen, P. T. Cloning of the complete coding region for human protein phosphatase inhibitor 2 using the two hybrid system and expression of inhibitor 2 in E. coli. FEBS Lett. 340: 93-98, 1994. [PubMed: 8119416] [Full Text: https://doi.org/10.1016/0014-5793(94)80179-7]
Huang, F. L., Glinsmann, W. H. Separation and characterization of two phosphorylase phosphatase inhibitors from rabbit skeletal muscle. Europ. J. Biochem. 70: 419-426, 1976. [PubMed: 188646] [Full Text: https://doi.org/10.1111/j.1432-1033.1976.tb11032.x]
Majer, M., Mott, D. M., Mochizuki, H., Rowles, J. C., Pedersen, O., Knowler, W. C., Bogardus, C., Prochazka, M. Association of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians. Diabetologia 39: 314-321, 1996. [PubMed: 8721777] [Full Text: https://doi.org/10.1007/BF00418347]
Permana, P. A., Mott, D. M. Genetic analysis of human type 1 protein phosphatase inhibitor 2 in insulin-resistant Pima Indians. Genomics 41: 110-114, 1997. [PubMed: 9126490] [Full Text: https://doi.org/10.1006/geno.1997.4649]
Prochazka, M., Mochizuki, H., Baier, L. J., Cohen, P. T. W., Bogardus, C. Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its major role in insulin resistance in Pima Indians. Diabetologia 38: 461-466, 1995. [PubMed: 7796987] [Full Text: https://doi.org/10.1007/BF00410284]
Sakagami, H., Kondo, H. Molecular cloning of the cDNA for rat phosphatase inhibitor-2 and its wide gene expression in the central nervous system. J. Chem. Neuroanat. 8: 259-266, 1995. [PubMed: 7669271] [Full Text: https://doi.org/10.1016/0891-0618(95)00051-8]
Sanseau, P., Jackson, A., Alderton, R. P., Beck, S., Senger, G., Sheer, D., Kelly, A., Trowsdale, J. Cloning and characterization of human phosphatase inhibitor-2 (IPP-2) sequences. Mammalian Genome 5: 490-496, 1994. [PubMed: 7949733] [Full Text: https://doi.org/10.1007/BF00369318]