Members of the TGF-beta superfamily exhibit various biological activities, and perturbations of their signaling are linked to certain clinical disorders including cancer. The role of TGF-beta signaling as a tumor suppressor pathway is best illustrated by the presence of inactivating mutations in genes encoding TGF-beta receptors and Smads in human carcinomas. This perspective is further support...

The bone morphogenetic protein (BMP) signaling pathway regulates a wide range of cellular responses in metazoans. A key step in the canonical BMP signaling is the phosphorylation and activation of transcription factors Smad1, Smad5, and Smad8 (collectively Smad1/5/8) by the type I BMP receptors. We previously identified PPM1A as a phosphatase toward dephosphorylation of all receptor-regulated S...

The Ski family of nuclear oncoproteins represses TGF-beta signaling through interactions with the Smad proteins. The crystal structure of the Smad4 binding domain of human c-Ski in complex with the MH2 domain of Smad4 reveals specific recognition of the Smad4 L3 loop region by a highly conserved interaction loop (I loop) from Ski. The Ski binding surface on Smad4 significantly overlaps with tha...

Phosphorylation of Smads is a crucial regulatory step in the signal transduction pathway initiated by bone morphogenetic proteins (BMPs). Although the dephosphorylation events terminating the pathway in the nucleus have been characterized, little is known about the dephosphorylation of Smads in the cytoplasm. In a proteomic screen for proteins interacting with the BMP type-II receptor, we found...

TGFb inhibits adipocyte differentiation, yet is expressed by adipocytes. The function of TGFb in adipogenesis, and its mechanism of action, is unknown. To address the role of TGFb signaling in adipocyte differentiation, we characterized the expression of the TGFb receptors, and the Smads which transmit or inhibit TGFb signals, during adipogenesis in 3T3-F442A cells. We found that the cell-surfa...

Tumor suppressor Smad4 is the common signaling effector in the transforming growth factor β (TGF-β) superfamily. Phosphorylated regulatory Smads (R-Smads) interact with Smad4, and the complex translocates into the nucleus to regulate gene transcription. Proper TGF-β signaling requires precise control of Smad functions. Smurfs have been shown to mediate the degradation of R-Smads but not the com...

We previously demonstrated that bone morphogenetic proteins (BMPs) induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1. Transcription factors Smads mediate transforming growth factor-beta signaling and the ATF/CREB family transcription factor ATF-2 has recently been shown to act as a common target of the Smad and the TAK1 pathways. We here examin...

Intercellular signaling by transforming growth factor-beta (TGF-beta) proteins coordinates developmental decisions in many organisms. A receptor complex and Smad signal transducers are required for proper responses to TGF-beta signals. We have taken a phylogenetic approach to understanding the developmental evolutionary history of TGF-beta signaling pathways. We were interested in detecting evo...

The SMAD (small mother against decapentaplegic) family comprises transcription factors that function as signal transducers of TGFbeta (transforming growth factor) superfamily members. The number of studies showing expression, activation or involvement of both SMAD and TGFbeta family members in cardiovascular diseases is constantly rising. In this context, the position of SMADs in the diseased h...

OBJECTIVE To explore the potential cardioprotective mechanism of Shenfu injection (SFI) against heart failure (HF) by attenuating myocardial fibrosis and cardiac remodeling. METHODS AND RESULTS Four weeks after myocardial infarction (MI), adult male Sprague Dawley rats were randomized for 4-week treatment with Valsartan, SFI, or vehicle. Echocardiography and hemodynamics were applied to evalu...