Research Program

Our current research focuses on Smad-mediated and non-Smad mechanisms of TGF-β signaling, and their roles in epithelial and mesenchymal differentiation, and in epithelial-mesenchymal transition.

Upon ligand binding to the receptor complex, Smads regulate transcription in cooperation with DNA-binding, sequence-specific transcription factors, and co-activators and co-repressors. Now that we have insight into the mechanisms of transcription activation and repression by Smads, we aim to understand the functional crosstalk of Smads with epigenetic regulation of gene expression and methyl transferases. TGF-β proteins also activate non-Smad signaling pathways, and we aim to define the mechanisms of TGF-β-induced activation of the Akt-TOR pathway, resulting in translation regulation, and TGF-β-induced Erk MAP kinase signaling, and their roles in the cell’s response to TGF-β. Finally, we are examining the regulation of receptor presentation and activity at the cell surface and how this regulation affects the TGF-β response.

Considering the key roles of the TGF-β family in cell and tissue differentiation, and in development, we address the roles of TGF-β family signaling, through Smad and non-Smad pathways, in epithelial and mesenchymal differentiation. We are particularly interested in the roles of these pathways in epithelial-mesenchymal differentiation, primarily in carcinoma progression, and the initiation of TGF-β and BMP signaling at the level of the cell surface receptor complexes, where different receptor complex differently control the TGF-β/BMP response. For more information, see an outline of ongoing and future projects.

Some History

Since 1983, our lab has pursued research on the molecular, cell, and tissue biology of TGF-β and TGF-β. The research on TGF-β has recently been winding down, and we now focus primarily on the mechanisms of signaling induced by TGF-β family proteins and the roles of these signaling mechanisms in epithelial and mesenchymal differentiation, including epithelial-mesenchymal transition.

Following the cDNA cloning of TGF-β, now known as TGF-β1, it became rapidly apparent that TGF-β1 would serve as prototype for a large TGF-β family with important roles in normal development, cancer progression and other diseases. Among the past "highlights" of this lab are (1) the cDNA cloning of TGF-β1, the first member of the TGF-β family, and of TGF-β3; (2) the demonstration that TGF-β1 expression is often upregulated in tumor development; (3) the demonstration that TGF-β can induce epithelial-mesenchymal transition, an important step for the tumor cell in the acquisition of an invasive phenotype leading to metastasis; (4) the identification of the first type I TGF-β receptor; (5) the identification of the TGF-β Smads and their role in TGF-β-induced transcription; (6) the mechanism of TGF-β-induced activation of Smads as signaling effectors; (7) the elucidation of important aspects of Smad-activated transcription; (8) the characterization of mechanisms of TGF-β-induced transcription repression through Smads; (9) the characterization of the role of TGF-β signaling in osteoblast differentiation and bone development, and myoblast differentiation; (10) the activation of Akt-TOR signaling, its effect on cell size and in epithelial-mesenchymal transition in response to TGF-β; (11) the discovery that inhibitory Smad methylation initiates TGF-β and BMP signaling.