Joan Massagué, Ph.D.

Specialty:

Cancer

Institution:

Chair, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center

Other Title:

Executive Committee, Geoffrey Beene Cancer Research Center, Memorial Sloan-Kettering Cancer Center

Notes:

We are interested in how growth factors, signaling pathways, and gene expression programs control normal cell proliferation and cancer cell metastasis. The development and maintenance of multicellular organisms requires tight control over the proliferation, differentiation, movement, organization and death of their constituent cells. Intricate molecular communication networks have evolved to control these processes. Our work is focusing on how cells receive, read and relay such signals, and how disruptions in these processes lead to tumor formation and cancer metastasis. We are approaching these questions through the rich venue provided by the transforming growth factor- (TGFb) pathway, as well as through the direct identification of metastasis genes and functions.

With nearly forty related members in the human genome, TGFb represents one of the most prominent and functionally versatile families of cytokines. This family -the TGFbs, nodals, activins, bone morphogenetic proteins (BMPs), myostatins, and anti-Muellerian hormoneexert profound effects on every aspect of cell behavior. Produced by many cell types or restricted to just a few, different TGFb family members guide early stages of embryo development and tissue homeostasis throughout life. We uncovered key steps in this signaling pathway by identifying the TGFb and BMP receptors and elucidating their mechanism of activation . These receptors are serine/threonine kinases and their substrates are the Smad transcription factors. We showed that Smad C-terminal phosphorylation by TGFb and BMP receptor kinases, and Smad linker phosphorylation by MAPK, GSK3 and other protein kinases, are key events in Smad regulation. We are identifying Smad interactions with transcription cofactors and ubiquitin ligases that are supported by these phosphorylation events. These findings are paving the way for new discoveries on the function and network integration of the TGFb and BMP pathways.