We study transforming growth factor-ß (TGF-ß) signal transduction, transcriptional regulation and cell cycle control.
TGF-ß and related polypeptides, including activins and bone morphogenetic proteins (BMPs), constitute the largest cytokine family, possessing fascinating features. They are multifunctional, regulating many aspects of cellular processes. For example, TGF-ß potently inhibits cell proliferation by causing cell cycle arrest at the G1 phase. In fact, TGF-ß is the most relevant physiological inhibitor of cell proliferation and therefore is a potent tumor suppressor at early stage of tumorigenesis. TGF-ß also regulates cell differentiation, adhesion, motility and apoptosis. TGF-ß family members are evolutionarily conserved and play an essential role in the development and homeostasis of virtually every tissue in organisms ranging from fruit flies to humans. Accordingly, inactivating mutations in several components of the TGF-ß signaling pathways have been found to cause human disorders, such as cancer.
TGF-ß signals through transmembrane serine/threonine kinase receptors. It binds and brings together two classes of receptors, the type I and type II receptors. The TGF-ß type II receptor is constitutively active. It transphosphorylates the type I receptor, which then plays a major role in specifying downstream events, leading to various biological responses largely through transcriptional regulation of a variety of genes that play crucial roles in determining cell fate.
Smad proteins can transduce the TGF-ß signal from the cell surface to the nucleus. Smads are directly phosphorylated by the TGF-ß family receptor kinases upon ligand stimulation. Following phosphorylation. Smads form heteromeric complexes, accumulate in the nucleus, and regulate transcription in association with other cofactors. Importantly, Smads are tumor suppressors. They are mutated in pancreatic and colon carcinomas and several other types of cancers. Thus, Smad proteins directly link transcriptional regulation with tumorigenesis.
Our current research is focused on the characterization of proline-directed kinases, which include cyclin-dependent kinases (CDKs) and MAP kinase superfamily, on phosphorylation of Smad proteins. We also study the mechanisms of how Smad transcriptional activities are regulated by several Smad-interacting proteins that we identified.