Aging-related attenuation of EGF receptor signaling is mediated in part by increased protein tyrosine phosphatase activity.
Exp Cell Res
; 289(2): 359-67, 2003 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-14499637
ABSTRACT
As fibroblasts near senescence, their responsiveness to external signals diminishes. This well-documented phenomenon likely underlies physiological deterioration and limited tissue regeneration in aging individuals. Understanding the underlying molecular mechanisms would provide opportunities to ameliorate these situations. A key stimulus for human dermal fibroblasts are ligands for the epidermal growth factor receptor (EGFR). We have shown earlier that EGFR expression decreases by about half in near senescent fibroblasts (Shiraha et al., 2000, J. Biol. Chem. 275 (25), 19343-19351). However, as the cell responses are nearly absent near senescence, other aging-related signal attenuation changes must also occur. Herein, we show that EGFR signaling as determined by receptor autophosphorylation is diminished over 80%, with a corresponding decrease in the phosphorylation of the immediate postreceptor adaptor Shc. Interestingly, we found that this was due at least in part to increased dephosphorylation of EGFR. The global cell phosphotyrosine phosphatase activity increased some threefold in near senescent cells. An initial survey of EGFR-associated protein tyrosine phosphatases (PTPases) showed that SHP-1 (PTPIC, HCP, SHPTP-1) and PTPIB levels are increased in parallel in these cells. Concomitantly, we also discovered an increase in expression of receptor protein tyrosine phosphatase alpha (RPTPalpha). Last, inhibition of protein tyrosine phosphatases by sodium orthovanadate in near senescent cells resulted in increased EGFR phosphorylation. These data support a model in which, near senescence, dermal fibroblasts become resistant to EGFR-mediated stimuli by a combination of receptor downregulation and increased signal attenuation.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Regulación hacia Arriba
/
Proteínas Tirosina Fosfatasas
/
Senescencia Celular
/
Receptores de Superficie Celular
/
Proteínas Adaptadoras Transductoras de Señales
/
Fibroblastos
/
Receptores ErbB
Tipo de estudio:
Prognostic_studies
Límite:
Humans
/
Male
/
Newborn
Idioma:
En
Revista:
Exp Cell Res
Año:
2003
Tipo del documento:
Article
País de afiliación:
Estados Unidos