Disease relevance of Pea15a

• In vivo analysis of an eventual PEA-15 regulation in astrocytes was performed using a model of astrogliosis occurring along motor neurons degeneration, the transgenic mouse expressing the mutant G93A human superoxyde-dismutase-1, a model of amyotrophic lateral sclerosis [1].
• Here, we show that, differently from glioma cell lines, glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15 [2].
• Overexpression of PEA-15 in breast cancer cells resulted in growth inhibition, reduction in DNA synthesis, and onset of caspase-8-dependent apoptosis [3].

High impact information on Pea15a

• PEA-15 is a multifunctional protein that modulates signaling pathways which control cell proliferation and cell death [4].
• PEA-15 expression in Chinese hamster ovary cells resulted in an increased mitogen-activated protein kinase kinase and ERK activity [5].
• PEA-15 is a small, death effector-domain (DED)-containing protein that was recently demonstrated to inhibit tumor necrosis factor-alpha-induced apoptosis and to reverse the inhibition of integrin activation due to H-Ras [5].
• The ability of PEA-15 to simultaneously inhibit apoptosis and potentiate Ras-to-Erk signaling may be of importance for oncogenic processes [5].
• Finally, the effects of PEA-15 on integrin signaling are separate from those on ERK activation [5].

Biological context of Pea15a

• These results show that PEA-15 provides a potential mechanism during development for distinguishing between diverse extracellular death-inducing signals that culminate either in apoptosis or in survival [6].
• Parallel to the increase in expression levels, phosphorylation of PEA-15 also increased during development [7].
• We observed a marked up-regulation of PEA-15 in reactive astrocytes that had developed throughout the ventral horn of the lumbar spinal cord of the transgenic mice [1].
• Identification of a novel, alternatively spliced isoform and single nucleotide polymorphisms in the murine Pea-15 gene [8].
• Death effector domain protein PEA-15 potentiates Ras activation of extracellular signal receptor-activated kinase by an adhesion-independent mechanism [5].

Anatomical context of Pea15a

• One such target, which we previously described, is PEA-15, a protein kinase C substrate associated with microtubules [9].
• The 15-kDa phosphoprotein enriched in astrocytes (PEA-15) inhibits Fas-mediated apoptosis and increases tumor necrosis factor receptor-1 (TNF-R1)-mediated apoptosis in the same cell type in a ligand-dependent manner [6].
• PEA-15 was found mainly in the cytosol, but its protein kinase C-phosphorylated form, Pb, was also detectable in association with the membrane and remained with the fraction that contains stabilized microtubules [7].
• Expression of MAT1/PEA-15 mRNA isoforms during physiological and neoplastic changes in the mouse mammary gland [10].

Associations of Pea15a with chemical compounds

• This led us to investigate if PEA-15 expression could be involved in astrocytic protection against deleterious effects of TNF [11].
• Furthermore, PEA-15 expression leads to an increase in Ras guanosine 5'-triphosphate loading [5].

Other interactions of Pea15a

• Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate [7].

References