Research in the Guan lab is focused on three particular areas: mTOR, the Hippo pathway, and Autophagy.
mTOR
Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that is part of the mTOR complex 1 (mTORC1), a master regulator that senses and responds to amino acid availability to control cell growth and autophagy. Multiple signals modulate mTORC1 activity, including growth factors, cellular stress, energy status, and amino acids. Although amino acids are a key environmental stimulus, exactly how they are sensed and regulate mTORC1 activity is not fully understood. Recent work in the Guan lab has focused on trying to better understand how amino acids are sensed and contribute to mTORC1 activation.
(Jewell JL, et al. Science, 2015.)
The Hippo pathway
Originally identified in Drosophila, the Hippo pathway is evolutionally conserved and regulates tissue homeostasis and organ size. In mammals, the Hippo pathway consists of the kinase cascade of MST1/2 and LATS1/2. When the Hippo pathway is activated, LATS1/2 phosphorylate the Hippo pathway downstream effectors YAP and TAZ, which results in YAP/TAZ sequestration in the cytoplasm, ubiquitination, and degradation. However, when the Hippo pathway is inactivated, YAP/TAZ are dephosphorylated and translocate to the nucleus, where they act as transcriptional co-activators. They interact with the TEAD1-4 family members to initiate gene expression promoting cell proliferation and growth. Many signals act upstream of the Hippo pathway to activate YAP/TAZ, including serum, growth factors, and hormones acting via GPCRs. Although dysregulation of YAP/TAZ have been strongly implicated in many types of human cancers and diseases, and increased YAP/TAZ expression and nuclear localization is often correlated with increased risk of metastasis and decreased prognosis, few mutations in Hippo pathway components have been identified. Therefore, work in the Guan lab has focused on identifying novel upstream components which may contribute to dysregulation of YAP/TAZ under pathological conditions.
(Yu FX, et al. Cell, 2015.)
Autophagy
The ability of cells to respond to changes in nutrient availability is essential for maintaining metabolic homeostasis and viability. One of the key cellular responses to nutrient withdrawal is autophagy. Recently, there has been a rapid expansion in our knowledge of the molecular mechanisms involved in the regulation of mammalian autophagy induction in response to depletion of key nutrients. Intracellular amino acids, ATP, and oxygen levels are intimately tied to the cellular balance of anabolic and catabolic processes. Signaling from key nutrient-sensitive kinases mTORC1 and AMP-activated protein kinase (AMPK) is essential for the nutrient sensing of the autophagy pathway. Recent advances have shown that the nutrient status of the cell is largely passed on to the autophagic machinery through the coordinated regulation of the ULK and VPS34 kinase complexes. Identification of extensive crosstalk and feedback loops converging on the regulation of ULK and VPS34 can be attributed to the importance of these kinases in autophagy induction and maintaining cellular homeostasis.