Disease relevance of PEA15

• Finally, PEA15 by itself suppressed colony formation in breast and ovarian cancer cell lines, in which E1A is known to have antitumor activity [1].
• Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians [2].
• In the U373MG glioma cells, blocking Akt also reduced PED/PEA-15 levels and induced sensitivity to tumor necrosis factor-related apoptosis-inducing ligand apoptosis [3].
• PED mediates AKT-dependent chemoresistance in human breast cancer cells [4].
• Ophthalmoscopic and angiographic features present at the initial visit which were associated with the development of NVM and poor final visual acuity were: sensory retinal detachment; increased size of PED; hot spot; late filling; notching; and irregular filling [5].

Psychiatry related information on PEA15

• Eugenio, into four classes: Anorexia Nervosa (AN), Nervous Bulimia (NB), Binge Eating Disorders (BED) and Psychogenic Eating Disorders that are Not Otherwise Specified (PED-NOS) [6].

High impact information on PEA15

• Searching for molecules potentially able to block DR death-inducing signaling complex (DISC), we found that primitive neural cells expressed high levels of the death effector domain-containing protein PED (also known as PEA-15) [7].
• Overexpression of the PED/PEA-15 gene may contribute to insulin resistance in glucose uptake in type 2 diabetes [8].
• PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus [8].
• The PED gene maps on human chromosome 1q21-22 [8].
• Antibiotic-resistance markers also were used to tag the a gene complex in MAT-1 strains (phleomycin) and the b gene complex in MAT-2 strains (hygromycin) [9].

Chemical compound and disease context of PEA15

• Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells [10].
• Immunohistochemical localization of tyrosinase was examined with a monoclonal antibody (MoAb MAT-1) against human tyrosinase on routine formalin-fixed paraffin-embedded sections of 3 normal skin specimens, 15 melanocytic tumors (6 pigmented nevi, 3 juvenile melanomas and 6 malignant melanomas) and 3 non-melanocytic tumors [11].

Biological context of PEA15

• By analysis of 22 Pimas, including 13 diabetic subjects, we detected four single nucleotide polymorphisms (SNPs) in the non-coding regions of PEA15, including three frequent variants that were in allelic disequilibrium, and one variant found only in a single Pima [2].
• The PEA15 locus is composed of four exons spanning approximately 10.2kb of genomic DNA, flanked upstream by an potentially expressed Alu element, downstream by the H326 gene, and is located within 250kb of KCNJ9 [2].
• In PED-expressing 293 cells (293(PED)), inhibition of apoptosis upon growth factor deprivation was paralleled by decreased phosphorylation of JNK1/2 [12].
• In these cells, expression of PED to levels comparable with those occurring in normal adult cells inhibits apoptosis induced by growth factor deprivation and by exposure to H(2)O(2) or anisomycin [12].
• Consistent with this hypothesis, we showed that E1A dramatically down-regulated the expression of the ERK1/2 nuclear export factor PEA-15 [13].
• PEA15 is a novel AMPK substrate. AMPK activation and phosphorylation of PEA15 at Ser116 promotes PEA anti-apoptotic function, thus facilitating mammosphere formation [14].

Anatomical context of PEA15

• RSK2 and PEA-15 (phosphoprotein enriched in astrocytes, 15 kDa) co-precipitated from cells and were colocalized in the cytoplasm [15].
• In MCF-7 and HeLa cells, a fivefold overexpression of PED/PEA-15 blocked FasL and TNFalpha apoptotic effects [16].
• Finally, we used a novel anti-phospho-specific PEA-15 antibody to establish that PEA-15 is phosphorylated in situ in normal mammary epithelium [17].
• Exposure of untransfected C5N keratinocytes and transfected HEK293 cells to phorbol esters (12-O-tetradecanoylphorbol-13-acetate (TPA)) increased PED/PEA-15 cellular content and enhanced its phosphorylation at serine 116 in a time-dependent fashion [18].
• We demonstrate that B lymphocytes obtained from patients with B-CLL express high levels of PED [19].

Associations of PEA15 with chemical compounds

• The PEA15 gene encoding a protein kinase C substrate is widely expressed, and its overexpression may contribute to impairment of glucose uptake [2].
• PEA15 is located within a region on human 1q linked with type 2 diabetes in both Pima Indians and Caucasians [2].
• RSK2 binds the COOH terminus of PEA-15 and does not interact with its NH2-terminal death effector domain [15].
• The death effector domain of PEA-15 is involved in its regulation of integrin activation [20].
• Stimulations of astrocytes known to increase PKC activity, i.e. noradrenaline, or its inhibition by decreasing extracellular calcium concentrations, staurosporine, or desensitization following long term treatment with TPA, induced a phosphorylation or a dephosphorylation of PEA-15, respectively [21].
• In euglycaemic FDR of type 2 diabetic subjects, PEA15 expression was inversely correlated with insulin sensitivity (r = -557, p = 0.01) [22].
• All these findings suggest that disruption of the PED/PEA-15-PLD1 molecular interaction enhances insulin sensitivity in skeletal muscle cells and indicate that PED/PEA-15 as an important target for type 2 diabetes [23].
• The involvement of PED in the refractoriness to TRAIL-induced cell death was investigated by silencing PED expression in TRAIL-resistant NSCLC cells with small interfering (si) RNAs: transfection with PED siRNA, but not with cFLIP siRNA, sensitized cells to TRAIL-induced cell death [24].

Physical interactions of PEA15

• Furthermore, purified PEA-15 bound in vitro translated RSK2, suggesting that these proteins interact directly [15].
• PEA-15 binding to ERK1/2 MAPKs is required for its modulation of integrin activation [25].
• The regulation of ERK2 by PEA-15 is appraised in the light of a simple equilibrium-binding model for reversible ERK2 nucleoplasmic-cytoplasmic shuttling, which elaborates on the theory of Burack and Shaw (J. Biol. Chem. 280, 3832-3837; 2005) [26].

Enzymatic interactions of PEA15

• Protein kinase B/Akt and AMPK binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action [3] and PMID: 25096718.

Regulatory relationships of PEA15

• Second, PEA-15 inhibits RSK2 kinase activity by 50% [15].
• Our findings suggest that noncoding SNPs in CASQ1 alter diabetes susceptibility, either by a direct effect on CASQ1 gene expression or perhaps by regulating a nearby gene such as PEA15 [27].
• These ERK2 mutants blocked the ability of PEA-15 to reverse suppression of integrin activation [25].
• Akt down-regulates ERK1/2 nuclear localization and angiotensin II-induced cell proliferation through PEA-15 [28].

Other interactions of PEA15

• Multiple members of the mitogen-activated protein kinase family are necessary for PED/PEA-15 anti-apoptotic function [12].
• Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation [12].
• These results can be attributed to two effects of PEA-15 on RSK2 [15].
• PEA-15 does not bind to RSK1 and therefore exhibits some binding specificity [15].
• A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation [28].

Analytical, diagnostic and therapeutic context of PEA15

• The expression of a maturation-associated gene, Mat1, was induced in both cotyledons and hypocotyl/radicle tissues of somatic embryos after 72 h desiccation [29].
• We evaluated the performance of the AQ by comparing donor deferrals for medical history (MHD), physical examination findings (PED), and reactive screening and/or confirmatory tests (RSCT) for viral markers among AQ-ineligible and AQ-eligible donors and separately among AQ-eligible donors who received AQ or FQ [30].
• MED/PED reported greater comfort than family physicians in complex internal medicine issues, but less than internists in intensive care and geriatric consultation [31].
• Locating the specific primers in different positions relative to the common primer yielded PCR products of 812 or 418 bp from MAT-1 and MAT-2 isolates, respectively [32].
• We show by genetic mapping of vic and MAT loci with AFLP markers and by sequence analysis of MAT loci that this diversification was due to selective acquisition by O. novo-ulmi of the MAT-1 and vic loci from another species, Ophiostoma ulmi [33].

References