Ongoing, Future and Possible Projects

Ongoing, future and possible projects.
Our overall goal is to understand the early events of TGF-β/BMP receptor activation at the cell surface, the differential control of Smad and non-Smad signaling in response to TGF-β, the mechanisms of non-Smad activation in response to TGF-β, and the roles of these mechanisms in TGF-β-induced epithelial-mesenchymal transition (EMT).

Functional interactions of methyltransferases with Smads.
We found that Smads associate with lysine and arginine methyltransferases. These interactions allow for inducible Smad methylation, and for methylation to participate in TGF-β- or BMP-induced signaling. We reported that BMP-induced Smad6 methylation on Arg by PRMT5 initiates and enables BMP-induced Smad signaling. We also found that Smads can recruit methyltransferases to target genes, where they participate in transcription control. Further studies on the functional interactions of Smads with methyltransferases will provide insight into the roles of methylation in TGF-β/BMP signaling.

Control of TGF-β receptor presentation at the cell surface and TGF-β responsiveness.
We found that most TGF-β receptors reside intracellularly and that signaling, in particular in response to Akt activation, controls the levels of TGF-β receptors at the cell surface and thus the responsiveness to TGF-β. Thus, Akt activation rapidly induces a strong upregulation of the cell surface TGF-β receptor levels, resulting in increased TGF-β responsiveness, and thus enhances the sensitivity of cells to EMT. These findings may be of high relevance for cancer progression. We aim to further define the underlying mechanisms.

Differential control of non-Smad signaling by cell surface TGF-β receptors.
We aim to gain better insight into how TGF-β induces non-Smad signaling pathways, in particular Erk MAPK and PI3K-Akt-mTOR signaling, at the level of the cell surface receptors. We found that the TGF-β receptor complexes that initiate these non-Smad signaling pathways are different from those that activate Smad signaling, and that cells differentially control the activation of non-Smad versus Smad signaling pathways. The adaptor protein ShcA plays an important role in the differential distribution of receptor complexes and activation of these pathways by TGF-β, which may relate to the ability of TGF-β receptors to phosphorylate on Tyr. Consequently, ShcA and the differential distribution of cell surface TGF-β receptor complexes are determinants of the EMT response. We aim to define the underlying mechanisms.

Participation of TGF-β signaling in the response to insulin.
Consistent with Akt’s ability to induce the appearance of TGF-β receptors at the cell surface, we found that insulin, which is the standard therapy for diabetes and a strong inducer of Akt activation, promotes increased levels of TGF-β receptors at the cell surface and enhances autocrine TGF-β responsiveness. This increased responsiveness results in participation of the TGF-β response in the cell response to insulin, which may be of substantial relevance for the control of EMT, and in fibrosis and cancer progression. Studies are underway to better define the participation of the TGF-β response in the response to insulin, both in cell culture and in vivo.