Definition of smad3 phosphorylation events that affect malignant and metastatic behaviors in breast cancer cells.
Cancer Res
; 74(21): 6139-49, 2014 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-25205100
ABSTRACT
Smad3, a major intracellular mediator of TGFß signaling, functions as both a positive and negative regulator in carcinogenesis. In response to TGFß, the TGFß receptor phosphorylates serine residues at the Smad3 C-tail. Cancer cells often contain high levels of the MAPK and CDK activities, which can lead to the Smad3 linker region becoming highly phosphorylated. Here, we report, for the first time, that mutation of the Smad3 linker phosphorylation sites markedly inhibited primary tumor growth, but significantly increased lung metastasis of breast cancer cell lines. In contrast, mutation of the Smad3 C-tail phosphorylation sites had the opposite effect. We show that mutation of the Smad3 linker phosphorylation sites greatly intensifies all TGFß-induced responses, including growth arrest, apoptosis, reduction in the size of putative cancer stem cell population, epithelial-mesenchymal transition, and invasive activity. Moreover, all TGFß responses were completely lost on mutation of the Smad3 C-tail phosphorylation sites. Our results demonstrate a critical role of the counterbalance between the Smad3 C-tail and linker phosphorylation in tumorigenesis and metastasis. Our findings have important implications for therapeutic intervention of breast cancer.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Transformação Celular Neoplásica
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Proteína Smad3
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Transição Epitelial-Mesenquimal
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article