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Research: Structural biology of regulator molecules in cell growth control and cell adhesion

Associate Chair of Research & Operations
Gary F. Liebscher Distinguished
Professor of Biochemistry and Biophysics

(PhD – Yale University)



  • Award for Excellent in Basic Science Mentoring – 2023
  • Gary F. Liebscher Distinguished Professorship – 2017
  • Battle Distinguished Cancer Research Award – 2014
  • Phillip & Ruth Hettleman Prize – 2001
  • Jefferson Pilot Award – 1998


GTPases: Aberrant regulation RAS and RHO GTPases is linked to a variety of disease states, including cancer, cardiovascular and neurological disorders. RAS, in particular, has been a topic of intense investigation, as oncogenic RAS mutations cause constitutive RAS activation and are prevalent in cancer. We have a longstanding history studying RAS proteins. In our earlier studies, we applied novel four dimensional nuclear magnetic resonance (NMR) approaches to determine the first solution structure of the RAS proto-oncogene. Subsequently, my group at the University of North Carolina identified and solved the NMR solution structure of a novel RAS binding site in the RAF kinase, that is required for RAF activation of the mitogen activated protein kinase cascade. Our work has also elucidated how post-translational modifications of RAS, in particular, cysteine oxidation and ubiquitin modification lead to RAS activation. Through these efforts, our lab developed novel chemical ligation and radical detection methods to characterize RAS post-translational modifications. Importantly, redox and ubiquitin modification of RAS contributes to RAS-mediated tumorigenesis. Our lab also showed that other members of the RAS superfamily (e.g., RHO GTPases) are regulated by these post-translational modifications, indicating conservation of these important regulatory mechanisms within the RAS superfamily of GTPases. We have recently extended these studies to investigate additional lysine modifications (acetylation, methylation) in RAS proteins. A current research interest in our lab lies in characterizing how residue and site-specific mutation differences in Ras proteins lead to distinct signaling and tumorigenic signatures. In a recent paper with the Sharpless lab (UNC), we characterized two different oncogenic Ras mutations to elucidate why one activating mutation promotes Melanoma whereas the other does not. Understanding these differences could lead to mutation specific anti-cancer therapies. We have most recently initiated NMR structural studies on the heterotrimeric Gai subunit, in collaboration with the Dohlman lab at UNC. Heterotrimeric G proteins are molecular switches that stimulate intracellular signalling cascades in response to activation of G-protein-coupled receptors (GPCRs) by extracellular stimuli. Our efforts here are centered on identification and characterization of inhibitors and mutations that activate and deactivate the Ga subunit.

Cell Adhesion Proteins: Our laboratory studies tumor suppressor (Vinculin) and tumor promoter (FAK, paxillin, palladin) proteins that control cell morphology and motility. Deregulation of cell motility plays an important role in cell metastasis, often the leading cause of cancer deaths. Our research efforts have elucidated protein-protein and protein-membrane interactions critical for regulated cell movement. Our group’s most recent studies of the cell adhesion protein, Vinculin, have focused on the Vinculin tail domain (Vt) and binding interactions with inositol phospholipids and actin. We have identified Vt regions important for phospholipid binding and membrane insertion, actin binding and actin bundling. We identified and characterized Vt variants that specially disrupt actin binding, and in collaboration with Clare Waterman’s group (NHLBI, NIH), applied super-resolution cellular microscopy approaches to analyze the role of Vinculin in integrating F-actin and focal adhesion dynamics. We then showed that Vinculin functions as a molecular clutch to extract energy from the actin cytoskeleton and use it to move the whole cell across a substrate. We also found that coordinate binding of actin with talin promotes vinculin activation. Actin binding to Vinculin also plays a key role in the sub-cellular distribution of Vinculin within focal adhesions. Although models for how Vinculin recognizes F-actin had been reported, our identification of a new actin binding interface on Vt, led us to examine alternative models for the Vt/actin complex. We have recently obtained one of the highest resolution cryo-electron microscopy (EM) reconstructions of a protein/actin complex (Vt/actin complex) currently available, in collaboration with the Alushin lab at NIH. Our structure is consistent with the new or alternative actin interface proposed by our lab, and provides new insights into actin induced conformational changes in Vinculin that promote Vinculin dimerization and actin filament bundling. Our current efforts are geared at understanding the structure of the actin-induced dimer, how the Vinculin dimer regulates actin reorganization and how the splice variant, Metavinculin, coordinates with Vinculin to reorganize actin filaments. We are also studying how Vinculin inserts in the membrane through specific interactions with the inositol phospholipid, PIP2, and how this interaction regulates Vinculin localization, activation and focal adhesion turnover.

Research Tools

Our laboratory employs multidisciplinary approaches to investigate these problems. While our main structural tool is high field NMR spectroscopy, we also employ other biophysical and biochemical methods including various computer modeling and computational approaches, fluorescence spectroscopy, biochemical characterization of binding interactions and enzyme activity. Most of our studies are conducted in collaboration with laboratories that focus on molecular and cellular biological aspects of these problems. This allows us to direct cell-based adhesion, motility, signaling and transformation analyses.


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Lab Contact:

Lab Room: 3100A-B Genetic Medicine
Lab Phone: (919) 966-6781

Sharon Campbell, PhD ​Principal Investigator ​Professor of Biochemistry & Biophysics