Ongoing, Future and Possible Projects

Functional interactions of methyl transferases with Smads

We previously characterized the mechanisms of how Smads, in response to TGF-β, activate or repress transcription of target genes through functional interactions with DNA-binding transcription factors and coregulators. We recently found that Smads physically and functionally interact with a variety of methyl transferases... read more

Roles of IRF-3 and IRF-7 in the TGF-β response

We have shown that the transactivation domains of IRF-3/7 and Smads show a remarkable structural similarity, and that their activation results from phosphorylation events at corresponding locations... read more

TGF-β-induced Akt-TOR and Erk MAP kinase activation and their roles in EMT

We have shown that TGF-β induces Akt-TOR signaling, leading to regulation of translation and cell size, and that this pathway also regulates the increased migration and invasion associated with epithelial-mesenchymal transition. We also showed that TGF-β induces Erk MAP kinase activation, through direct phosphorylation of the Shc adaptor protein on tyrosines by the type I TGF-β receptor... read more

Smad signaling and the mesenchymal differentiation plasticity

Smads function as cell-intrinsic regulators of differentiation programs and respond to extracellular cues presented by TGF-β family proteins through autocrine and paracrine signaling mechanisms. We have previously elucidated basic mechanisms of Smad-mediated repression that explain the inhibition of adipocyte, myoblast and osteoblast differentiation in response to TGF-β... read more

Smad signaling in embryonic stem cell pluripotency and EMT

TGF-β family proteins play important roles in the maintenance of the pluripotent state of embryonic stem cells, and in the first differentiation decision of embryonic stem cells in culture, i.e. the generation of fibroblast-like niche cells from the epithelial embryonic cells... read more

Mechanism and roles of TGF-β receptor sumoylation

We found that, in response to TGF-β, the type I receptor is post-translationally modified by addition of a SUMO polypeptide, and that this sumoylation is dependent on the phosphorylation state of the receptor. Further, the receptor sumoylation enhances the signaling capacity of the TGF-β receptors... read more

Regulation of ectodomain shedding of TGF-β receptors

We found that the cell surface levels of the type I TGF-β receptors, and thus of the functional TGF-β receptor complexes, are regulated by the transmembrane metalloprotease TACE. Activation of TACE, which is often upregulated in carcinomas, results in ectodomain shedding of the TGF-β type I receptor, and, consequently, downregulation of the TGF-β responsiveness... read more

Mechanisms of glucose-induced TGF-β signaling, leading to increased cell size

High glucose has long been known to induce an increase in cell size and protein content. We found that this increase is at least in part mediated by activation of TGF-β signaling through the Akt-TOR pathway, which in turn results from a rapid increase in cell surface presentation of the TGF-β receptors, and a rapid activation of TGF-β ligand by metalloproteases... read more