Overview
The main interest of our laboratory is to understand molecular principles of signal transduction events. We investigate them at the level of enzymatic function of protein kinases, molecular structure of signaling proteins and dynamics of signaling pathways. Our current focus is on understanding how membrane-associated kinases, such as Receptor Tyrosine Kinases, assemble into functional complexes and interface with the plasma membrane to generate specific and unique signaling outputs. We also investigate alternative non-catalytic roles of kinase scaffolds (pseudokinases) and seek to identify small molecule inhibitors that target these poorly understood kinase functions in human diseases.
Current Areas of Interest:
Structure-function studies of receptor tyrosine kinase activation mechanism
We use X-ray crystallography and cryo-electron microscopy (cryo-EM) to gain high resolution insights into ligand-dependent activation of the Receptor Tyrosine Kinase complexes, propagation of conformational changes in the receptor domains across the plasma membrane, and interaction of the receptors with their downstream effectors. To validate our structural models, we use quantitative cell-based functional assays, such as phospo-flow cytometry.
Understanding how membrane participates in cellular signaling
By using various technologies of the in vitro membrane reconstitution, we use synthetic approaches to build the minimal signaling units comprising Receptor Tyrosine Kinases in vitro. This allows us to study how the stoichiometry and kinetic properties of receptor activation are regulated by the membrane environment.
Direct visualization of receptor activation events at cell surface
Spatial and temporal aspects of receptor tyrosine kinase activation in cells decide about the signaling outcome of receptor activation. To capture and understand these essential parameters, in collaboration with Bo Huang’s lab at UCSF we are developing tools for super resolution imaging of receptor activation in response to growth factors in cells.
Understudied protein kinases
Most of research focuses on few protein kinases leaving large portion of human kinome unexplored. Around 10% of all kinases in the human genome do not even have catalytic activity, but are essential for cellular homeostasis and frequently misregulated in human diseases. We are interested in elucidating the structural and functional basis for the understudied and atypical kinase functions, and ultimately in their modulation by small molecules with the goal of developing effective therapeutics.