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| DED: death effector domain, amino acid region 3-81, Pfam: PF01335 (Sanger); NES: leucine-rich nuclear export sequence, amino acid region 7-17; MT: microtubule-binding region, amino acid region 98-107, and 122-129; PLD-1 binding region: phospholipase D1 binding site, amino acid region 1-24; ERK binding site: amino acid position 74, 121, 123, and 129; RSK2 binding site: amino acid position 123; Serine 104: phosphorylation site by PKC; Serine 116: phosphorylation site by AKT or CaKMII. |
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Description | PEA-15 is a 130-amino-acid protein with a predicted molecular mass of 15054 daltons and a calculated isoelectric point of 5.12. |
Expression | Ovary, breast, brain, placenta, liver, eye, lung, heart, endothelial cells, pancreas, testis, uterus, adrenal gland, prostate gland, kidney, spleen, and astrocytes. |
Localisation | Cytoplasm. PEA-15 has a leucine-rich nuclear export sequence (NES), which is required for predominantly localizing in the cytoplasm (Formstecher et al., 2001). |
Function | PEA-15 is a ubiquitously expressed protein that exists in non-phosphorylated, mono-phosphorylated, and double-phosphorylated forms (Danziger et al., 1995). PEA-15 does not have an enzymatic domain but serves as a binding molecule in protein complexes. PEA-15 is an endogenous substrate that depends on two distinct serine sites: Ser104, which is phosphorylated by protein kinase C (PKC) (Kubes et al., 1998), and Ser116, which is phosphorylated by Ca2+/calmodulin kinase II (CaMKII) (Kubes et al., 1998) or by AKT (Trencia et al., 2003). At its NH2 terminus, PEA-15 has a PLD-interacting region, which enhances PLD 1 stability and activity (Zhang et al., 2000), and a death effector domain (DED), which enables interaction with DED-containing signaling proteins, including Fas-associated protein with death domain (FADD) and FADD-like IL-1β-converting enzyme (Peter et al., 1999). At its COOH terminus, PEA-15 has a microtubule-binding region, which regulates the stability of tubulins (Danziger et al., 1995). ERK inhibition. PEA-15 can bind to ERK and sequester it in the cytoplasm. The resulting inhibition of ERK's translocalization into the nucleus blocks ERK-dependent transcriptional activity and cell proliferation (Formstecher et al., 2001). Apoptosis and anti-apoptosis. PEA-15 interacts with different DED-containing proteins such as FADD and FLICE and inhibits Fas/TNFR1-induced apoptosis by preventing formation of the death-inducing signaling complex (DISC) (Condorelli et al., 1999; Song et al., 2006). On the other hand, under different cellular stresses, PEA-15 acts as a substrate of Omi/HtrA2, which is a proapoptotic mitochondrial serine protease; it results in reducing anti-apoptotic action of Omi/HtrA2 and triggering apoptotic programs (Trencia et al., 2004). Metabolism. In skeletal muscle and adipose cells, PEA-15 binds to PLD1 and enhances PKC-α activity, thereby inducing resistance to insulin action in glucose uptake (Condorelli et al., 1998). Invasion. A high expression level of PEA-15 is correlated with low invasive behavior of breast cancer (Glading et al., 2007). PEA-15's prevention of ERK's nuclear localization results in reduced invasion capability in breast cancer. Tumorigenicity. In human breast cancers, low levels of PEA-15 expression correlated with high nuclear grade and with negative hormone receptor status. Overexpression of PEA-15 in breast cancer cells resulted in growth inhibition, reduction in DNA synthesis, and onset of caspase-8-dependent apoptosis (Bartholomeusz et al., 2010). In transgenic mice with overexpression of PEA-15, its expression level had a significant impact on skin tumor development upon chemically induced skin carcinogenesis (Formisano et al., 2005). In in vitro studies, PEA-15 enhanced Ras-MAPK/ERK signaling in the presence of constitutively active H-Ras and drove transformation of kidney epithelial cells (Sulzmaier et al., 2012; Ramos et al., 2000). |
Homology | The mouse and human sequences are conserved. In both species, the 3' UTR of the 2,5-kb PEA15 cDNA contains the proto-oncogene MAT1 (Tsukamoto et al., 2000). |
PEA-15 inhibits tumorigenesis in an MDA-MB-468 triple-negative breast cancer xenograft model through increased cytoplasmic localization of activated extracellular signal-regulated kinase. |
Bartholomeusz C, Gonzalez-Angulo AM, Kazansky A, Krishnamurthy S, Liu P, Yuan LX, Yamasaki F, Liu S, Hayashi N, Zhang D, Esteva FJ, Hortobagyi GN, Ueno NT. |
Clin Cancer Res. 2010 Mar 15;16(6):1802-11. Epub 2010 Mar 9. |
PMID 20215547 |
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PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. |
Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalo P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F. |
Oncogene. 1999 Aug 5;18(31):4409-15. |
PMID 10442631 |
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Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate. |
Danziger N, Yokoyama M, Jay T, Cordier J, Glowinski J, Chneiweiss H. |
J Neurochem. 1995 Mar;64(3):1016-25. |
PMID 7861130 |
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The major astrocytic phosphoprotein PEA-15 is encoded by two mRNAs conserved on their full length in mouse and human. |
Estelles A, Yokoyama M, Nothias F, Vincent JD, Glowinski J, Vernier P, Chneiweiss H. |
J Biol Chem. 1996 Jun 21;271(25):14800-6. |
PMID 8662970 |
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Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. |
Formisano P, Perruolo G, Libertini S, Santopietro S, Troncone G, Raciti GA, Oriente F, Portella G, Miele C, Beguinot F. |
Oncogene. 2005 Oct 27;24(47):7012-21. |
PMID 16044159 |
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PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. |
Formstecher E, Ramos JW, Fauquet M, Calderwood DA, Hsieh JC, Canton B, Nguyen XT, Barnier JV, Camonis J, Ginsberg MH, Chneiweiss H. |
Dev Cell. 2001 Aug;1(2):239-50. |
PMID 11702783 |
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PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma. |
Gawecka JE, Geerts D, Koster J, Caliva MJ, Sulzmaier FJ, Opoku-Ansah J, Wada RK, Bachmann AS, Ramos JW. |
Int J Cancer. 2012 Oct 1;131(7):1556-68. doi: 10.1002/ijc.27415. Epub 2012 Jan 31. |
PMID 22213050 |
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PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2. |
Glading A, Koziol JA, Krueger J, Ginsberg MH. |
Cancer Res. 2007 Feb 15;67(4):1536-44. |
PMID 17308092 |
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Endothelin induces a calcium-dependent phosphorylation of PEA-15 in intact astrocytes: identification of Ser104 and Ser116 phosphorylated, respectively, by protein kinase C and calcium/calmodulin kinase II in vitro. |
Kubes M, Cordier J, Glowinski J, Girault JA, Chneiweiss H. |
J Neurochem. 1998 Sep;71(3):1307-14. |
PMID 9721757 |
|
The death receptors. |
Peter ME, Scaffidi C, Medema JP, Kischkel F, Krammer PH. |
Results Probl Cell Differ. 1999;23:25-63. (REVIEW) |
PMID 9950028 |
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Death effector domain protein PEA-15 potentiates Ras activation of extracellular signal receptor-activated kinase by an adhesion-independent mechanism. |
Ramos JW, Hughes PE, Renshaw MW, Schwartz MA, Formstecher E, Chneiweiss H, Ginsberg MH. |
Mol Biol Cell. 2000 Sep;11(9):2863-72. |
PMID 10982386 |
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Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. |
Song JH, Bellail A, Tse MC, Yong VW, Hao C. |
J Neurosci. 2006 Mar 22;26(12):3299-308. |
PMID 16554480 |
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PED mediates AKT-dependent chemoresistance in human breast cancer cells. |
Stassi G, Garofalo M, Zerilli M, Ricci-Vitiani L, Zanca C, Todaro M, Aragona F, Limite G, Petrella G, Condorelli G. |
Cancer Res. 2005 Aug 1;65(15):6668-75. |
PMID 16061647 |
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PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D. |
Sulzmaier FJ, Valmiki MK, Nelson DA, Caliva MJ, Geerts D, Matter ML, White EP, Ramos JW. |
Oncogene. 2012 Jul 26;31(30):3547-60. doi: 10.1038/onc.2011.514. Epub 2011 Nov 21. |
PMID 22105357 |
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Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15. |
Trencia A, Fiory F, Maitan MA, Vito P, Barbagallo AP, Perfetti A, Miele C, Ungaro P, Oriente F, Cilenti L, Zervos AS, Formisano P, Beguinot F. |
J Biol Chem. 2004 Nov 5;279(45):46566-72. Epub 2004 Aug 24. |
PMID 15328349 |
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Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action. |
Trencia A, Perfetti A, Cassese A, Vigliotta G, Miele C, Oriente F, Santopietro S, Giacco F, Condorelli G, Formisano P, Beguinot F. |
Mol Cell Biol. 2003 Jul;23(13):4511-21. |
PMID 12808093 |
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Expression of MAT1/PEA-15 mRNA isoforms during physiological and neoplastic changes in the mouse mammary gland. |
Tsukamoto T, Yoo J, Hwang SI, Guzman RC, Hirokawa Y, Chou YC, Olatunde S, Huang T, Bera TK, Yang J, Nandi S. |
Cancer Lett. 2000 Feb 28;149(1-2):105-13. |
PMID 10737714 |
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Expression of phosphoprotein enriched in astrocytes 15 kDa (PEA-15) in astrocytic tumors: a novel approach of correlating malignancy grade and prognosis. |
Watanabe Y, Yamasaki F, Kajiwara Y, Saito T, Nishimoto T, Bartholomeusz C, Ueno NT, Sugiyama K, Kurisu K. |
J Neurooncol. 2010 Dec;100(3):449-57. Epub 2010 May 9. |
PMID 20455002 |
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Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians. |
Wolford JK, Bogardus C, Ossowski V, Prochazka M. |
Gene. 2000 Jan 4;241(1):143-8. |
PMID 10607908 |
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Regulation of expression of phospholipase D1 and D2 by PEA-15, a novel protein that interacts with them. |
Zhang Y, Redina O, Altshuller YM, Yamazaki M, Ramos J, Chneiweiss H, Kanaho Y, Frohman MA. |
J Biol Chem. 2000 Nov 10;275(45):35224-32. |
PMID 10926929 |
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