"Intercellular Force Transduction"

Deborah Leckband, Ph.D.
Reid T. Milner Professor of Chemical Sciences
Professor of Chemistry
University of Illinois

ABSTRACT
Our research focuses on determining how intercellular force transduction contributes to human pathologies such as ventilator induced lung injury and malignant transformation in breast cancer.  Specifically we focus on cadherins, which are essential intercellular adhesion proteins and mechanical and signalling hubs in all tissues. Cadherins regulate tissue barriers, cell segregation in morphogenesis, and proliferation. We use mechanical perturbations, together with biochemical and biophysical approaches to determine how force fluctuations in tissues regulate these cadherin-dependent tissue functions. We established two force-transduction mechanisms that regulate cell mechanics and transcriptional activation. One mechanism involves a cytoplasmic protein, alpha catenin, which links cadherin complexes to actin. Under increased tension, alpha catenin exposes a binding site for vinculin, which scaffolds actin remodelling at perturbed junctions. In epithelia, we also demonstrated that force-loaded cadherin receptors activate the epidermal growth factor receptor, EGFR and a kinase cascade that in turn activates integrins. In epithelia, E-cadherin and EGFR regulate contact-inhibited proliferation. Our studies show that increased intercellular tension disrupts the complex to potentiate EGF-dependent activation of EGFR and downstream Erk1/2, thus directly coupling mechanics to pro-proliferative signalling. Both the alpha catenin and kinase-mediated cascades also operate in other tissues, but involve tissue-specific cadherin/growth factor receptor pairs. Our findings reveal that cadherins, growth factor receptors, and integrins form a mechanosensitive network that regulates force sensitive tissue functions. I will discuss the broader implications of our findings for vascular function, breast cancer, and stem cell differentiation.

BIO
Deborah Leckband is the Reid T. Milner professor of Chemical Sciences at the University of Illinois. She earned a PhD in biophysical chemistry at Cornell, and did postdoctoral work with Robert Langer and then with Jacob Israelachvili.  She has appointments in Chemical and Biomolecular Engineering, Chemistry, and Bioengineering at the University of Illinois. She is a former Head of Chemical and Biomolecular Engineering and directed the Bioengineering graduate program at Illinois. She held/holds elected positions in the BMES and is a BMES Fellow. She is a Fellow of AIMBE and the American Chemical Society. Deborah pioneered the use of surface force measurements to study proteins at interfaces to identify molecular scale interfacial properties of biomaterials. Her group discovered unexpected relationships between structures of adhesion proteins and their adhesive functions. Her current research focuses on multiscale investigations of force transduction at intercellular junctions. Her group was one the first to discover force transducton at cell-to-cell junctions. They continue to build on those initial findings, with a particular focus on how force transduction impacts tissue functions in development and disease. This multidisciplinary  research program involves a wide range of collaborations with cell biologists, clinical researchers, tissue engineers, and biophysicists.

DISTINCTIONS / AWARDS
Fellow, Biomedical Engineering Society (BMES), 2014
Fellow, American Chemical Society, 2009
Reid T. Milner Professor, University of Illinois, UC, 2006-
Fellow, American Association for the Advancement of Science, 2005
Fellow, American Institute for Medical and Biological Engineering, 2005
James W. Westwater Professor, University of Illinois, UC, 2004-2006
Britton Chance Distinguished Lecturer, University of Pennsylvania, 2004

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