Transforming growth factor beta (TGF-β) is a multifunctional protein hormone that signals through a complex system of receptors, Smads and a constantly growing array of Smad and receptor interacting proteins. The need for this complexity becomes clear in light of the diverse roles of TGF-β and the TGF-β superfamily in nearly all aspects of biology in all stages of life. Throughout life, TGF-β family members control a variety of physiological processes including immune responses, bone formation, and wound healing to name a few. In additoin, TGF-β and proteins involved in TGF-β signaling are tumor suppressor genes that are lost or inactivated in a variety of epithelial and lymphoid neoplasms. Our laboratory takes a combined genomic, proteomic and mouse models approach to understanding the complexity that underlies the cell type specific and context specific nature of TGF-β signaling. Specifically, using mice that harbor a targeted disruption of the Smad3 gene, we have identified a number of biological and cellular responses to TGF-β that are independent of Smad3 function, and that occur in a cell type specific or context dependent fashion. Using mRNA expression profiling in these systems, we are identifying genes that are transcriptionally regulated independent of Smad signaling. Coupled with these genomic approaches, we are also employing state of the art phosphoproteome profiling and expression proteome profiling techniques to identify novel substrates of the TGF-β receptor kinases.

In addition to using these proteome profiling techniques to answer basic science questions of signal transduction, we are also applying these approaches to a second clinically focused project, namely the identification of disease markers for diagnosis or prognosis in a variety of disease states. This is a new project in the laboratory which is greatly facilitated by our close ties to the DUMC Clinical Molecular Diagnostics Laboratory.