Kunhong (Kevin) Xiao, MD, PhD

Research Associate Professor

E1355 Thomas E. Starzl Biomedical Science Tower
Pittsburgh, PA 15261
Phone: 412-648-1381
Fax: 412-648-1945


BM (Clinical Medicine), Beijing Medical University, 1993
PhD (Biochemistry & Molecular Biology), Oklahoma State University, 2003
Postdoctoral Fellow (Receptor Biology & Pharmacology), Duke University Medical Center, 2003-2008


Kunhong (Kevin) Xiao, MD, PhD
Figure 1 Figure 1
To understand the molecular mechanisms of β-arrestin-biased agonism from three distinct perspectives: receptor posttranslational medication, signaling network, and structural basis.
Dr. Xiao’s research focuses on the molecular mechanisms of GPCR signaling and pharmacology. GPCRs, the largest family of cell surface receptors, are crucial to human health and present a core target of modern medicine. These receptors regulate virtually all known physiological/pathophysiological processes in humans. The clinical significance of GPCRs relies on the fact that these receptors account for about 50% of all prescription drugs, with annual worldwide pharmaceutical sales in excess of $700 billion. In recent years, the discovery of β-arrestin (β-arr)-mediated signaling has led to a paradigm shift in GPCR biology and pharmacology. The newly discovered nature of two parallel pathways (G protein- vs. β-arr-mediated) signaling downstream of GPCRs makes it possible to activate selectively one pathway over another (termed biased agonism or functional selectivity). This concept of biased agonism provides the potential opportunity to develop an entirely new class of drugs---biased ligands, which can activate selectively a specific pathway, and thus trigger only particular effects at the physiological level (e.g., desired therapeutic outcomes and diminished side effects). Therefore, to understand the molecular mechanisms of biased agonism is of great significance.

During the past 10 years, Dr. Xiao elucidated the molecular mechanisms of biased agonism from different perspectives---receptor level regulation, signaling networks, and structural basis (Figure 1). Using cutting-edge and high-throughput MS-based proteomics, in combination with systems, chemical and structural biology, Dr. Xiao studied protein function, macromolecular interaction, and post-translational modifications downstream of β-arrs and GPCRs. His work provided a global view of GPCR signaling and a better understanding of the molecular mechanisms of β-arr biased agonism of GPCRs (Figure 2). The findings from these studies have opened up new avenues for the rational design of more efficient and specific drugs as an approach to individualized medicine.

Dr. Xiao also is interested in delineating the structure-function relations of multi-protein complexes important for GPCR signaling and pharmacology.
Figure 2Figure 2
A system’s view of β-arrestin-mediated GPCR signaling.
 As our understanding of GPCR signaling evolves from simple, one-way pathways to more complicated networks, investigating protein complexes has become the keystone of GPCR research. One of the most direct ways to flesh out the function of these protein complexes is to study their structure. However, the structural characterization, achieved by standard methods such as X-ray crystallography or NMR of receptor protein complexes poses numerous challenges.

In recent years, Dr. Xiao developed multiple MS-based structural strategies, for example, an orthogonal approach combining hydrogen-deuterium-exchange/MS (HDXMS), cross-linking/MS (CXMS) and disulfide trapping, to reveal information regarding the overall architecture of protein complexes, detailed information of the interfaces, and structural dynamics during complex formation (Figure 3). The information offers new insight into the mechanistic-structural-functional relationships of protein complexes and provides a potential platform for developing novel therapeutic interventions.
Figure 3
Figure 3
The modeling was based on HDXMS analysis, chemical cross-link based mapping, disulphide trapping and electron microscope studies. (A) Enlarged view of the β2AR- βarr1 interface. (B) Illustration of the two-step interaction between a GPCR and βarr1.
Dr. Xiao is actively engaged in the development of new MS-based, high-throughput proteomics and systems biology technologies for therapeutic target identification and biomarker discovery. The ultimate goal of this line of research is to 1) identify novel molecules and pathways that have the potential to become therapeutic targets for the treatment of diseases; 2) identify novel biomarkers and more sensitive methods for disease early stage detection and diagnosis.

Journal Articles

Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao XJ, Apirat C, Knapp S, Xiao K, Campbell SL, Thiele DJ and Counter CM. Copper is required for oncogenic BRAF signaling and tumorigenesis. Nature 509:492-496, 2014.
Shukla A, Westfield G, Xiao K, Reis RI, Huang LY, Tripathi-Shukla P, Qian J, Li S, Blanc A, Oleskie AN, Dosey AM, Su M, Liang CR, Gu LL, Shan JM, Chen X, Hanna R, Choi M, Yao XJ, Klink BU, Kahsai AW, Sidhu S, Koide S, Penczek PA, Kossiakoff AA, Woods V, Kobilka BK, Skiniotis G and Lefkowitz RJ. Visualization of arrestin recruitment by a G- protein-coupled receptor. Nature 512:218-22, 2014.

Kahsai AW, Rajagopal S, Sun J and Xiao K.  Monitoring protein conformational changes and dynamics using stable-isotope labeling and mass spectrometry. Nature Protocols 9:1301–1319, 2014.
Shukla A, Manglik A, Kruse A, Xiao K, Reis A, Tseng W, Staus D, Hilger D, Uysal S, Huang L, Paduch M, Tripathi-Shukla P, Koide A, Koide S, Weis W, Kossiakoff A, Kobilka B and Lefkowitz RJ. Structure of active β-arrestin1 bound to a G protein-coupled receptor phosphopeptide. Nature 497:137-141, 2013.
Kahsai AW, Xiao K, Rajagopal S, Ahn S, Shukla AK, Sun J, Oas TG and Lefkowitz RJ.   Multiple ligand-specific conformations of the β2-adrenergic receptor. Nature Chemical Biology 7:692-700, 2011.
Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CL, Rajagopal S, Bressler EA, Hara RM, Shenoy SK, Gygi SP and Lefkowitz RJ.   Distinct GRK phosphorylation sites on the β2AR: A “bar code” which differentially encodes β-arrestin functions. Science Signaling 4:ra51, 2011.
Xiao K and Shenoy SK. β2AR lysosomal trafficking is regulated by ubiquitination of lysyl residues in two distinct receptor domains. Journal of Biological Chemistry 286: 12785-12795, 2011. 

Sponsored Research

Structural Basis of PTH Receptor Function - 4/1/2018 - 3/31/2022
NIH - R01DK116780
Functional Polarity of PTH Receptor Signaling: Cellular and Molecular Mechanisms - 8/20/2017 - 6/30/2021
NIH - R01DK111427