Integrin alpha2beta1 inhibits Fas-mediated apoptosis in T lymphocytes by protein phosphatase 2A-dependent activation of the MAPK/ERK pathway.
J Biol Chem
; 278(49): 48633-43, 2003 Dec 05.
Article
em En
| MEDLINE
| ID: mdl-13679375
ABSTRACT
The mechanisms by which T lymphocytes escape apoptosis during their activation are still poorly defined. In this study, we elucidated the intracellular signaling pathways through which beta1 integrins modulate Fas-mediated apoptosis in T lymphocytes. In experiments done in Jurkat T cells and activated peripheral blood T lymphocytes, engagement of alpha2beta1 integrin with collagen type I (Coll I) was found to significantly reduce Fas-induced apoptosis and caspase-8 activation; Annexin V binding and DNA fragmentation were reduced by approximately 42 and 38%, respectively. We demonstrated that the protective action of Coll I does not require new protein synthesis but was dependent on the activation of the MAPK/Erk pathway. Furthermore, we found that activation of protein phosphatase 2A (PP2A) by Coll I was required for both Coll I-mediated activation of Erk, and inhibition of Fas-induced caspase-8 activation and apoptosis. Other ligands of beta1 integrins, fibronectin (Fbn), and laminin (Lam), did not sustain significant Erk activation and had no effect on Fas-induced apoptosis. Taken together, these results provide the first evidence of a PP2A-dependent activation of the MAPK/Erk pathway downstream of alpha2beta1 integrin, which has a functional role in regulating Fas-mediated apoptosis in T lymphocytes. As such, this study emphasizes the potential importance that Coll I interactions may have on the control of T lymphocyte homeostasis and their persistence in chronic inflammatory diseases.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Apoptose
/
Fosfoproteínas Fosfatases
/
Receptor fas
/
Proteínas Quinases Ativadas por Mitógeno
/
Integrina alfa2beta1
Limite:
Humans
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article