RESUMO
Transforming growth factor-ß (TGFß) signaling is initiated by the type I, II TGFß receptor (TßRI/TßRII) complex. Here we report the formation of an alternative complex between TßRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TßRI induces spontaneous TßRI-dependent Smad and non-Smad signaling by stabilizing the active TßRI conformation and competing for the binding of the negative regulator FKBP12 to TßRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TßRI and decreases tumor growth in a xenograft mouse model. Inversely, targeted deletion of GPR50 in the MMTV/Neu spontaneous mammary cancer model shows decreased survival after tumor onset and increased tumor growth. Low GPR50 expression is associated with poor survival prognosis in human breast cancer irrespective of the breast cancer subtype. This describes a previously unappreciated spontaneous TGFß-independent activation mode of TßRI and identifies GPR50 as a TßRI co-receptor with potential impact on cancer development.
Assuntos
Neoplasias Mamárias Animais/prevenção & controle , Proteínas do Tecido Nervoso/fisiologia , Receptor do Fator de Crescimento Transformador beta Tipo I/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Endossomos/metabolismo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Proteínas Smad/metabolismo , Proteína 1A de Ligação a Tacrolimo/metabolismoRESUMO
Although E3 ubiquitin ligases are deemed to play key roles in normal cell function and homeostasis, whether their alterations contribute to cancer pathogenesis remains unclear. In this study, we sought to investigate potential mechanisms that govern WWP1/Tiul1 (WWP1) ubiquitin ligase activity, focusing on its ability to trigger degradation of TGFß type I receptor (TßRI) in conjunction with Smad7. Our data reveal that the WWP1 protein is very stable at steady states because its autopolyubiquitination activity is silenced due to an intra-interaction between the C2 and/or WW and Hect domains that favors WWP1 monoubiquitination at the expense of its polyubiquitination or polyubiquitination of TßRI. Upon binding of WWP1 to Smad7, this functional interplay is disabled, switching its monoubiquitination activity toward a polyubiquitination activity, thereby driving its own degradation and that of TßRI as well. Intriguingly, a WWP1 point mutation found in human prostate cancer disrupts this regulatory mechanism by relieving the inhibitory effects of C2 and WW on Hect and thereby causing WWP1 hyperactivation. That cancer-driven alteration of WWP1 culminates in excessive TßRI degradation and attenuated TGFß cytostatic signaling, a consequence that could conceivably confer tumorigenic properties to WWP1.
