RESUMO
The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-ß (TGF-ß) family signaling. I-Smads inhibit TGF-ß family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. However, how I-Smads interact with type I receptors is not well understood. In the present study, we found that Smad7 has two modes of interaction with type I receptors. One is through a three-finger-like structure in the MH2 domain, consisting of residues 331-361, 379-387, and the L3 loop. The other is through a basic groove in the MH2 domain (Mochizuki, T., Miyazaki, H., Hara, T., Furuya, T., Imamura, T., Watabe, T., and Miyazono, K. (2004) J. Biol. Chem. 279, 31568-31574). We also found that Smad6 principally utilizes a basic groove in the MH2 domain for interaction with type I receptors. Smad7 thus has an additional mode of interaction with TGF-ß family type I receptors not possessed by Smad6, which may play roles in mediating the inhibitory effects unique to Smad7.
Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteína Smad7/metabolismo , Animais , Células COS , Chlorocebus aethiops , Células Hep G2 , Humanos , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteína Smad6/genética , Proteína Smad6/metabolismo , Proteína Smad7/genéticaRESUMO
In mammals, two inhibitory Smads (I-Smads), Smad6 and Smad7, play pivotal roles in negative regulation of TGF-beta family signaling. Smad7 ubiquitously inhibits TGF-beta family signaling, whereas Smad6 inhibits signaling from the ALK-3/6 subfamily in preference to that from the ALK-1/2 and ALK-4/5/7 subfamilies of TGF-beta family type I receptors. In Drosophila, only one I-Smad, Dad, has been identified. Here we examined inhibitory effects of Dad on type I receptors in Drosophila. Dad inhibited Saxophone (ALK-1/2 orthologue) and Thickveins (ALK-3/6 orthologue) but not Baboon (ALK-4/5/7 orthologue). The differential modes of action of I-Smads in mammals and Drosophila are discussed.
Assuntos
Receptores de Ativinas/antagonistas & inibidores , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Ativinas/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Humanos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteína Smad4/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Bone morphogenetic proteins (BMPs) exhibit broad spectra of biological activities in various tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. BMPs are members of the transforming growth factor-beta (TGF-beta) family that bind to type II and type I serine-threonine kinase receptors, and transduce signals through Smad and non-Smad signalling pathways. Recent findings have revealed that BMP signalling is finely tuned by various mechanisms in both positive and negative fashions. Perturbations of BMP signalling pathways are linked to a wide variety of clinical disorders, including vascular diseases, skeletal diseases and cancer. Administration of recombinant BMP ligands and increasing endogenous expression of BMPs provide therapeutic effects on some diseases. The recent development of BMP receptor inhibitors may also prove useful for some clinical diseases induced by hyperactivation of the BMP signalling pathways.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas , Transdução de Sinais , Animais , Receptores de Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas/química , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Humanos , Ligantes , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Transforming growth factor-beta (TGF-beta) stimulates phosphorylation of TGF-beta type I receptor. This receptor is now shown to be sumoylated, leading to enhanced activation and modulation of the downstream Smad signalling pathway.
Assuntos
Regulação da Expressão Gênica , Proteína SUMO-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , Modelos Biológicos , Mutação , Metástase Neoplásica , Neoplasias/metabolismo , Fosforilação , Transdução de SinaisRESUMO
The inhibitory Smads, Smad6 and Smad7, play pivotal roles in negative regulation of transforming growth factor-beta (TGF-beta) family signaling as feedback molecules as well as mediators of cross-talk with other signaling pathways. Whereas Smad7 acts as a ubiquitous inhibitor of Smad signaling, Smad6 has been shown to effectively inhibit bone morphogenetic protein (BMP) signaling but only weakly TGF-beta/activin signaling. In the present study, we have found that Smad6 inhibits signaling from the activin receptor-like kinase (ALK)-3/6 subgroup in preference to that from the ALK-1/2 subgroup of BMP type I receptors. The difference is attributable to the interaction of Smad6 with these BMP type I receptors. The amino acid residues responsible for Smad6 sensitivity of ALK-3 were identified as Arg-238, Phe-264, Thr-265, and Ala-269, which map to the N-terminal lobe of the ALK-3 kinase domain. Although Smad6 regulates BMP signaling through multiple mechanisms, our findings suggest that interaction with type I receptors is a critical step in the function of Smad6.