Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/- mast cells.
Blood
; 112(12): 4646-54, 2008 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-18768391
ABSTRACT
Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutations in the NF1 locus, which encodes neurofibromin, a negative regulator of Ras. Patients with NF1 develop numerous neurofibromas, which contain many inflammatory mast cells that contribute to tumor formation. Subsequent to c-Kit stimulation, signaling from Ras to Rac1/2 to the MAPK pathway appears to be responsible for multiple hyperactive mast cell phenotypes; however, the specific effectors that mediate these functions remain uncertain. p21-activated kinase 1 (Pak1) is a downstream mediator of Rac1/2 that has been implicated as a positive regulator of MAPK pathway members and is a modulator of cell growth and cytoskeletal dynamics. Using an intercross of Pak 1(-/-) mice with Nf1(+/-) mice, we determined that Pak1 regulates hyperactive Ras-dependent proliferation via a Pak1/Erk pathway, whereas a Pak1/p38 pathway is required for the increased migration in Nf1(+/-) mast cells. Furthermore, we confirmed that loss of Pak1 corrects the dermal accumulation of Nf1(+/-) mast cells in vivo to levels found in wild-type mice. Thus, Pak1 is a novel mast cell mediator that functions as a key node in the MAPK signaling network and potential therapeutic target in NF1 patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas p21(ras)
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Genes da Neurofibromatose 1
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Proteínas Proto-Oncogênicas c-kit
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Proteínas Quinases Ativadas por Mitógeno
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Quinases Ativadas por p21
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Mastócitos
Limite:
Animals
Idioma:
En
Revista:
Blood
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos