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- Title
The death effector domain protein PEA-15 negatively regulates T-cell receptor signaling.
- Authors
Pastorino, Sandra; Renganathan, Hemamalini; Caliva, Maisel J.; Filbert, Erin L.; Opoku-Ansah, John; Sulzmaier, Florian J.; Gawecka, Joanna E.; Werlen, Guy; Shaw, Andrey S.; Ramos, Joe W.
- 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.
- Subjects
MITOGEN-activated protein kinases; T cells; PHOSPHOPROTEINS; CYTOPLASM; APOPTOSIS; DEATH receptors
- Publication
FASEB Journal, 2010, Vol 24, Issue 8, p2818
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.09-144295