Non-compensating roles between Nckalpha and Nckbeta in PDGF-BB signaling to promote human dermal fibroblast migration.
J Invest Dermatol
; 129(8): 1909-20, 2009 Aug.
Article
em En
| MEDLINE
| ID: mdl-19242519
ABSTRACT
Platelet-derived growth factor BB (PDGF-BB) is a Food and Drug Administration (FDA)-approved growth factor, acting as a mitogen and motogen of dermal fibroblasts (DFs), for skin wound healing. The two closely related SH2/SH3 adapter proteins, Nckalpha and Nckbeta, connect PDGF-BB signaling to the actin cytoskeleton and cell motility. The mechanism has not been fully understood. In this study, we investigated, side by side, the roles of Nckalpha and Nckbeta in PDGF-BB-stimulated DF migration. We found that cells expressing the PDGFRbeta-Y751F mutant (preventing Nckalpha binding) or PDGFRbeta-Y1009F mutant (preventing Nckbeta binding), DF cells isolated from Nckalpha- or Nckbeta-knockout mice, and primary human DF cells with RNA interference (RNAi) knockdown of the endogenous Nckalpha or Nckbeta all failed to migrate in response to PDGF-BB. Overexpression of the middle SH3 domain of Nckalpha or Nckbeta alone in human DFs also blocked PDGF-BB-induced cell migration. However, neither Nckalpha nor Nckbeta was required for the activation of the PDGF receptor, p21-activated protein kinase (Pak1), AKT, extracellular signal-regulated kinase (ERK) 1/2, or p38MAP by PDGF-BB. Although PDGF-BB stimulated the membrane translocation of both Nckalpha and Nckbeta, Nckalpha appeared to mediate Cdc42 signaling for filopodium formation, whereas Nckbeta mediated Rho signaling to induce stress fibers. Thus, this study has elucidated the independent roles and mechanisms of action of Nckalpha and Nckbeta in DF migration, which is critical for wound healing.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cicatrização
/
Fator de Crescimento Derivado de Plaquetas
/
Transdução de Sinais
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Proteínas Oncogênicas
/
Proteínas Adaptadoras de Transdução de Sinal
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Invest Dermatol
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos