MERIT Award Recipient: Joan Massagué, Ph.D.
Transforming Growth Factor-β Signal Transduction
The basic functions of an animal cell -- its metabolism, proliferation, differentiation, integration into the tissue structure, and eventual death -- are controlled by a dense network of protein growth factor signals. The transforming growth factor-β (TGF-β) family of growth factors is particularly prominent among this type of signal. TGF-β fosters tissue formation and growth during embryonic development in organisms as diverse as worms, fruit flies, and humans. In the adult, however, TGF-β delivers anti-proliferative and cell death signals. These responses help maintain normal tissue structure and function, and their loss contributes to tumor development: cancer cells that evade TGF-β-mediated growth inhibition may then use TGF-β to promote their own proliferative, invasive, and metastatic behavior. This project is devoted to defining the mechanisms by which TGF-β and related factors trigger regulatory signals in normal cells but fail to do so in cancer cells.
During the first decade of work on this project, we set the foundation for identifying the basic components of the TGF-β intracellular signaling pathway, including the Smad family of proteins that is essential for transmitting TGF-β signals. This goal was accomplished during the second decade of this project, supported by a MERIT award. In its third decade, supported by a renewed MERIT award, this project is devoted to defining the integration of the TGF-β/Smad pathway in the complex and diverse signaling networks of the cell, and the corruption of TGF-β signaling in cancer. We will address this general problem in several complementary ways by focusing on Smad proteins and their partners as nodes for signal integration. We will investigate how diverse signals control Smad function and degradation. Having identified key partners of Smads in the mediation of TGF-β anti-proliferative effects, we will determine their roles as modifiers of the cellular response to TGF-β. Further, we will investigate the biological significance of diverse cellular functions (tissue formation, metastasis, cell cycle arrest, negative feedback) that are controlled by intracellular mediators of TGF-β-triggered signals. We will also seek to identify new central components and regulators of the TGF-β/Smad pathway through the use of novel chemical, biochemical, and functional proteomics approaches. Through this work, we wish to furnish the field with a better understanding of the role of the TGF-β/Smad pathway in physiology and an improved ability to manage this pathway in tumor progression, metastasis and other disorders.