Xiaolei Su, PhD
|School||UCSF School of Medicine|
|Department||Cellular Molecular Pharmacology|
|Harvard University||Ph.D.||2012||Biological and Biomedical Sciences|
|Marine Biological Laboratory||Summer course||2009||Physiology|
|Peking University||B.S.||2006||Biological Sciences|
|Keystone Symposia||2015||Keystone Symposia Future of Science Fund Scholarship |
|Cancer Research Institute||2014
||2017||Cancer Research Institute Irvington Fellowship|
|Harvard University||2012||Richard J. Herrnstein Prize for dissertation|
|Marine Biological Laboratory||2009||Lola Ellis Robertson Endowed Scholarship|
|Peking University||2006||Graduates with honors|
|China Scholarship Council||2004||Hewlett-Packard Scholarship|
I have a long-term interest in exploring protein dynamics and understanding how spatial organization of molecules affects cell physiology. I did my PhD under the mentorship of David Pellman at Harvard. My graduate work aimed to address two long-standing questions in the field of cytoskeleton: 1. how are lengths of microtubule polymers matched to their cellular functions? 2. how are individual microtubules organized into complex structures like mitotic spindles? I focused on a universal microtubule length regulator kinesin-8. I discovered a tethering mechanism explaining the super-processivity of kinesin-8 on microtubules, which is essential for the motor to reach microtubule ends to control microtubule length and promotes chromosome congression during mitosis. The other part of my graduate work reveals a novel function of kinesin-8 in organizing microtubules and promoting spindle assembly. Using combined approaches of biochemistry, single molecule imaging and genetics, I found kinesin-8 contains a secondary microtubule binding domain on the tail, which mediates kinesin-8’s microtubule sliding activity in vitro and spindle pole separating function in vivo. These experiences trained me well in comprehensive skills of cell biology and strengthened my confidence in doing basic science as a future career.
As a postdoctoral fellow in Ron Vale's Lab at UCSF, I have been interested in understanding how protein clustering regulates the T cell receptor signaling, a question remained in the field for almost two decades. I led a team in the HHMI Summer Institute at the Marine Biological Laboratory to develop an in vitro reconstitution system for studying the mechanisms and functional consequences of T cell microclusters. We successfully reconstituted a TCR-LAT-actin signaling pathway on a synthetic membrane using 12 purified proteins. We found that T cell microclusters are phase separated structures formed through multivalent protein-protein interactions. These clusters enrich kinases but exclude phosphatases, thus promoting phosphorylation. The clusters also facilitate actin polymerization by recruiting and organizing actin regulators on the membrane. These findings connected phase transition, a classical phenomenon in physical chemistry, to the cell signaling field and provided a new perspective in understanding the mechanism of signal transduction.
My future research will follow two directions. 1. engineering T cell activation responses. My previous work suggested T cell activation is affected by protein clustering. I am developing an inducible protein clustering system based on the SunTag technology, aiming to alter the threshold of T cell activation. This will help to understand how T cells differentially respond to foreign versus self antigens. It could also provide new tools for T cell-based cancer immunotherapy. 2. Understanding endomembrane signaling. Cell surface signaling pathways have been well-studied whereas our knowledge about signaling events on the endomembrane system is very limited. I will use the in vitro reconstitution system I developed, together with live cell imaging to investigate the spatial organization of receptors, kinases, and phosphatase on the membrane of endoplasmic reticulum and nuclear envelope. I aim to understand how the interactions of these proteins regulate calcium flux, lipid transport, and transcription.
T cell activation, membrane-proximal signaling, endomembrane structure and function, phase transition, cytoskeletal dynamics
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