The death effector domain protein PEA‐15 negatively regulates T‐cell receptor signaling

Abstract

PEA-15 is a death effector domain-containing phosphoprotein that binds ERK and restricts it to the cytoplasm. PEA-15 also binds to FADD and thereby blocks apoptosis induced by death receptors. Abnormal expression of PEA-15 is associated with type II diabetes and some cancers; however, its physiological function remains unclear. To determine the function of PEA-15 in vivo, we used C57BL/6 mice in which the PEA-15 coding region was deleted. We thereby found that PEA-15 regulates T-cell proliferation. PEA-15-null mice did not have altered thymic or splenic lymphocyte cellularity or differentiation. However, PEA-15 deficient T cells had increased CD3/CD28-induced nuclear translocation of ERK and increased activation of IL-2 transcription and secretion in comparison to control wild-type littermates. Indeed, activation of the T-cell receptor in wild-type mice caused PEA-15 release of ERK. In contrast, overexpression of PEA-15 in Jurkat T cells blocked nuclear translocation of ERK and IL-2 transcription. Finally, PEA-15-null T cells showed increased IL-2 dependent proliferation on stimulation. No differences in T cell susceptibility to apoptosis were found. Thus, PEA-15 is a novel player in T-cell homeostasis. As such this work may have far reaching implications in understanding how the immune response is controlled.

Phosphorylation is the switch that turns PEA-15 from tumor suppressor to tumor promoter

“…Activation of the T cell through the T-cell receptor also starts signaling pathways leading to the phosphorylation of PEA-15 causing it to release ERK, which in turn induces the transcription of nuclear targets resulting in T-cell proliferation. 11 We also previously described that stimulation of Cos-7 cells and thymocytes Figure 1. PEA-15 is phosphorylated at serine 104 upon EGF stimulation.…”

“…10 It thereby prevents ERK mediated phosphorylation of nuclear substrates like transcription factors, leading to a decrease in proliferation. 11 At the same time PEA-15 does not block ERK activity itself and does not inhibit activation of cytoplasmic targets like the ribosomal S6 kinase isoform 2 (RSK2). It in fact mediates ERK driven RSK2 activation by acting as a scaffold to bring both proteins together.…”

PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D

“…PEA-15 negatively regulates H-Ras to ERK signaling and blocks H-Ras mediated proliferation signals by sequestering ERK in the cytoplasm (Formstecher et al 2001, Pastorino et al 2010). The ability of cells to grow in suspension is a hallmark of transformation.…”

Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

“…NF1 is a Ras GTPase Activating Protein whose loss in T cells impaired both development and peripheral function (Ingram et al, 2002). PEA-15 association with ERK prevents its translocation to the nucleus, but its loss does not impair T cell development (Formstecher et al, 2001; Pastorino et al, 2010). Other mechanisms, such as differences in the dimerization of Mek1 and Mek2, have also been reported to influence nuclear localization (Catalanotti et al, 2009).…”