Research / Clinical
Summary
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Kun-Liang Guan, Ph.D.
Professor, Pharmacology
Cancer Biology Program
Contact by Email
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Diseases/Research Topics
Hippo, mTOR, Rheb, TSC, YAP
Research in Dr. Guan's laboratory focuses on intracellular signal transduction in cell growth regulation and cancer biology.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of benign tumors in a wide range of tissues. Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for TSC disease. TSC1 and TSC2 proteins form a physical and functional complex.
Recent studies from Guan's laboratory demonstrate that TSC1/TSC2 functions to inhibit the mammalian target of rapamycin (mTOR), which is a central cell growth controller conserved from yeast to human. mTOR integrates a wide range of signals, including growth factors, nutrients, and stress conditions, to regulate cell growth and cell size.
Two distinct TOR complexes, TORC1 and TORC2, have been identified. These two TOR complexes phosphorylate different substrates and have distinct physiological functions. For example, TORC1 phosphorylates the ribosomal S6 kinase (S6K), thereby regulating translation and cell growth.
In contrast, TORC2 phosphorylates and activates AKT, a key kinase involved in cell growth and apoptosis. Guan and his team are interested in how mTOR is regulated by upstream signals, such nutrients and cellular energy levels. In addition, they are studying the mechanism of mTOR activation by the phosphatidyl inositol 3-kinase (PI3K).
The second project in his laboratory is studying the novel Hippo tumor suppressor pathway. Recent genetic studies in Drosophila have shown that the Hippo signaling pathway plays a key role in restricting organ size by controlling both cell proliferation and apoptosis. Components of the Hippo pathway are highly conserved in mammalian cells. Acting down stream of the Hippo pathway is the YAP oncogene, which encodes a transcription co-activator.
Their recent studies have shown that regulation of YAP by the Hippo pathway plays a critical role in cell contact inhibition. Furthermore, YAP is elevated in many human cancers. The main focus of this project is to elucidate the physiological regulation of the Hippo pathway and to understand how dysregulation of the pathway contributes to tumorigenesis.
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