Alternative titles; symbols
HGNC Approved Gene Symbol: PEA15
Cytogenetic location: 1q23.2 Genomic coordinates (GRCh38) : 1:160,205,384-160,215,372 (from NCBI)
PEA15 is a ubiquitously expressed 15-kD protein with broad antiapoptotic function. By virtue of its death effector domain (DED), PEA15 binds other DED-containing proteins, preventing formation of the death-inducing signaling complex and inhibiting activation of the caspase cascade (see CASP3; 600636) (summary by Trencia et al., 2004).
Astrocytes are involved in a variety of functions, including storage of glycogen and support for the migration and differentiation of neurons. They express membrane receptors which allow them to respond to extracellular signals. Activation of the receptors induces a cascade of events, such as the stimulation of protein kinases and the subsequent phosphorylation of target proteins. Araujo et al. (1993) identified a unique 15-kD protein in astrocytes that exists as a nonphosphorylated form and as 2 increasingly phosphorylated varieties. This protein, which they called PEA15, contains a consensus site for protein kinase C (PKC; e.g., 176960) and is an endogenous substrate for PKC.
Bera et al. (1994) isolated the mouse Mat1 gene and found that it can transform NIH 3T3 cells and the mammary epithelial cell line TM3. Hwang et al. (1997) noted that the HMAT1 gene (GenBank L37385), the human homolog of mouse Mat1, had been cloned. They stated that a 2.5-kb HMAT1 transcript had been detected in normal mammary epithelial cells and tumor cell lines; its expression levels were higher in breast cancer cell lines than in normal mammary epithelial cells.
Estelles et al. (1996) cloned 2 forms of mouse Pea15 cDNA that differ in the length of the 3-prime UTR; these likely represent transcripts generated by alternative polyadenylation. The authors found that the 3-prime UTR of the longer Pea15 cDNA contains the Mat1 protooncogene sequence. They proposed that the Mat1 cDNA is a partial sequence of the Pea15 gene and does not encode a protein. Northern blot analysis of rat tissues revealed 2 Pea15 transcripts which were expressed abundantly in the central nervous system and at lower levels in peripheral tissues. Estelles et al. (1996) also identified 2 forms of human PEA15 cDNA (GenBank X86809), which are the counterparts of the mouse Pea15 cDNAs. Northern blot analysis of human brain extracts detected both PEA15 transcripts. Several regions between the human and mouse 3-prime UTRs share more than 90% identity. The deduced 130-amino acid human and mouse PEA15 proteins are 96% identical. Danziger et al. (1995) showed that the Pea15 protein colocalizes with microtubules.
Using differential display to identify genes whose expressions are altered in tissues derived from type II diabetes mellitus (125853) patients compared with nondiabetic individuals, Condorelli et al. (1998) cloned cDNAs encoding PEA15, which they named PED for 'phosphoprotein enriched in diabetes.' The ubiquitously expressed 2.8-kb PED mRNA was overexpressed in fibroblasts, skeletal muscle, and adipose tissue from type II diabetics. Levels of the 15-kD PED phosphoprotein were also elevated in type II diabetic tissues. The authors demonstrated that transfection of a PED cDNA into differentiating L6 skeletal muscle cells increases the content of glucose transporter-1 (GLUT1; 138140) on the plasma membrane and inhibits insulin-stimulated glucose transport and cell surface recruitment of glucose transporter-4 (GLUT4; 138190). These effects were reversed by blocking PKC activity.
Wolford et al. (2000) demonstrated the PEA15 gene is not associated with type II diabetes mellitus in Pima Indians.
Using expression cloning, Ramos et al. (1998) identified PEA15 in a screen designed to isolate cDNAs that prevent Ras suppression of integrin activation. The authors concluded that PEA15 inhibits suppression downstream of MAP kinase via a pathway blocked by a dominant-negative form of R-Ras (165090). Cotransfection experiments showed that PEA15 mutants lacking the DED were unable to reverse Ras suppression of integrin activation.
Kitsberg et al. (1999) investigated whether PEA15 expression could be involved in astrocytic protection against deleterious effects of TNF (191160). Using in vitro assays, Kitsberg et al. (1999) determined that PEA15 interacts with 2 other DED-containing proteins, FADD (602457) and caspase-8 (CASP8; 601763), known to be apical adaptors of TNF apoptotic signaling. Using homologous recombination, Kitsberg et al. (1999) generated PEA15 null mice. Based on the analysis of primary astrocyte cultures from the PEA15 knockout mice, they concluded that PEA15 expression protects astrocytes from TNF-induced apoptosis.
Formstecher et al. (2001) reported that PEA15 blocks ERK (see 601795)-dependent transcription and proliferation by binding ERKs and preventing their localization in the nucleus. In transfected cells, the expression of PEA15 blocked the ability of ERK MAP kinase to phosphorylate and activate the transcription factor ELK1 (311040). Formstecher et al. (2001) concluded that the effect of PEA15 on ERK signaling was due to the binding of PEA15 to ERKs and the inhibition of their accumulation in the nucleus. Formstecher et al. (2001) identified a nuclear export sequence in PEA15 that is required to anchor ERK in the cytoplasm. They concluded that PEA15 can redirect the biologic outcome of MAP kinase signaling by regulating the subcellular localization of ERK MAP kinase.
Trencia et al. (2004) determined that the antiapoptotic effect of PEA15 was reversed by OMI (HTRA2; 606441)-mediated PEA15 degradation. OMI is a mitochondrial intermembrane serine protease that is released from mitochondria by apoptotic stimuli. OMI did not coprecipitate with PEA15 from HeLa cells under normal conditions. However, exposure of cells to ultraviolet C radiation resulted in cytosolic relocalization of OMI, interaction of OMI with PEA15, and PEA15 degradation. Pharmacologic inhibition of OMI serine protease activity or overexpression of PEA15 reduced cell sensitivity to ultraviolet C. Trencia et al. (2004) concluded that the caspase-independent cell death induced by cytoplasmic release of OMI is mediated by PEA15 degradation.
Ricci-Vitiani et al. (2004) found that human neural progenitor cells (NPCs) lacked expression of CASP8, and that absence of CASP8 provided resistance to DR ligand-induced apoptosis. Even in the presence of inflammatory cytokines, which induced CASP8 expression, DRs were unable to generate death signals in primitive neural cells. Exogenous expression of CASP8 did not trigger DR-induced apoptosis in NPCs, suggesting that, in addition to absence of CASP8, NPCs had a second mechanism to protect them from DR-induced cell death. Further analysis identified high expression of PEA15 in NPCs as another level of protection, as PEA15 localized in the death-inducing signaling complex and blocked CASP8 recruitment and activation.
Vaidyanathan et al. (2007) showed that PEA15 enhanced activation of ribosomal S6 kinase-2 (RSK2, or RPS6KA3; 300075) by increasing its association with ERK in a concentration-dependent manner. PEA15 increased RSK2 activity and CREB-mediated transcription, and this process was regulated by PEA15 phosphorylation. Phorbol ester stimulation of Pea15-null mouse lymphocytes resulted in impaired Rsk2 activation, which was rescued by exogenous Pea15 expression. Vaidyanathan et al. (2007) concluded that PEA15 functions as a scaffold to enhance ERK activation of RSK2, and that this activity is regulated by PEA15 phosphorylation.
Wolford et al. (2000) determined that the PEA15 gene contains 4 exons and spans approximately 10.2 kb of genomic DNA flanked upstream by a potentially expressed Alu element and downstream by the H326 gene.
By radiation hybrid mapping using STSs generated from PEA15 ESTs, Condorelli et al. (1998) localized the human PEA15 gene to chromosome 1q21-q22 between markers D1S2635 and D1S484. Hwang et al. (1997) mapped the HMAT1 gene to 1q21.1 by fluorescence in situ hybridization.
Araujo, H., Danziger, N., Cordier, J., Glowinski, J., Chneiweiss, H. Characterization of PEA-15, a major substrate for protein kinase C in astrocytes. J. Biol. Chem. 268: 5911-5920, 1993. [PubMed: 8449955]
Bera, T. K., Guzman, R. C., Miyamoto, S., Panda, D. K., Sasaki, M., Hanyu, K., Enami, J., Nandi, S. Identification of a mammary transforming gene (MAT1) associated with mouse mammary carcinogenesis. Proc. Nat. Acad. Sci. 91: 9789-9793, 1994. [PubMed: 7937892] [Full Text: https://doi.org/10.1073/pnas.91.21.9789]
Condorelli, G., Vigliotta, G., Iavarone, C., Caruso, M., Tocchetti, C. G., Andreozzi, F., Cafieri, A., Tecce, M. F., Formisano, P., Beguinot, L., Beguinot, F. PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. EMBO J. 17: 3858-3866, 1998. [PubMed: 9670003] [Full Text: https://doi.org/10.1093/emboj/17.14.3858]
Danziger, N., Yokoyama, M., Jay, T., Cordier, J., Glowinski, J., Chneiweiss, H. Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate. J. Neurochem. 64: 1016-1025, 1995. [PubMed: 7861130] [Full Text: https://doi.org/10.1046/j.1471-4159.1995.64031016.x]
Estelles, A., Yokoyama, M., Nothias, F., Vincent, J.-D., Glowinski, J., Vernier, P., Chneiweiss, H. The major astrocytic phosphoprotein PEA-15 is encoded by two mRNAs conserved on their full length in mouse and human. J. Biol. Chem. 271: 14800-14806, 1996. [PubMed: 8662970] [Full Text: https://doi.org/10.1074/jbc.271.25.14800]
Formstecher, E., Ramos, J. W., Fauquet, M., Calderwood, D. A., Hsieh, J.-C., Canton, B., Nguyen, X.-T., Barnier, J.-V., Camonis, J., Ginsberg, M. H., Chneiweiss, H. PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev. Cell 1: 239-250, 2001. [PubMed: 11702783] [Full Text: https://doi.org/10.1016/s1534-5807(01)00035-1]
Hwang, S., Kuo, W.-L., Cochran, J. F., Guzman, R. C., Tsukamoto, T., Bandyopadhyay, G., Myambo, K., Collins, C. C. Assignment of HMAT1, the human homolog of the murine mammary transforming gene (MAT1) associated with tumorigenesis, to 1q21.1, a region frequently gained in human breast cancers. Genomics 42: 540-542, 1997. [PubMed: 9205133] [Full Text: https://doi.org/10.1006/geno.1997.4768]
Kitsberg, D., Formstecher, E., Fauquet, M., Kubes, M., Cordier, J., Canton, B., Pan, G., Rolli, M., Glowinski, J., Chneiweiss, H. Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNF-alpha-induced apoptosis. J. Neurosci. 19: 8244-8251, 1999. [PubMed: 10493725] [Full Text: https://doi.org/10.1523/JNEUROSCI.19-19-08244.1999]
Ramos, J. W., Kojima, T. K., Hughes, P. E., Fenczik, C. A., Ginsberg, M. H. The death effector domain of PEA-15 is involved in its regulation of integrin activation. J. Biol. Chem. 273: 33897-33900, 1998. [PubMed: 9852038] [Full Text: https://doi.org/10.1074/jbc.273.51.33897]
Ricci-Vitiani, L., Pedini, F., Mollinari, C., Condorelli, G., Bonci, D., Bez, A., Columbo, A., Parati, E., Peschle, C., De Maria, R. Absence of caspase 8 and high expression of PED protect primitive neural cells from cell death. J. Exp. Med. 200: 1257-1266, 2004. [PubMed: 15545353] [Full Text: https://doi.org/10.1084/jem.20040921]
Trencia, A., Fiory, F., Maitan, M. A., Vito, P., Barbagallo, A. P. M., Perfetti, A., Miele, C., Ungaro, P., Oriente, F., Cilenti, L., Zervos, A. S., Formisano, P., Beguinot, F. Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15. J. Biol. Chem. 279: 46566-46572, 2004. [PubMed: 15328349] [Full Text: https://doi.org/10.1074/jbc.M406317200]
Vaidyanathan, H., Opoku-Ansah, J., Pastorino, S., Renganathan, H., Matter, M. L., Ramos, J. W. ERK MAP kinase is targeted to RSK2 by the phosphoprotein PEA-15. Proc. Nat. Acad. Sci. 104: 19837-19842, 2007. [PubMed: 18077417] [Full Text: https://doi.org/10.1073/pnas.0704514104]
Wolford, J. K., Bogardus, C., Ossowski, V., Prochazka, M. Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians. Gene 241: 143-148, 2000. [PubMed: 10607908] [Full Text: https://doi.org/10.1016/s0378-1119(99)00455-2]