We work on receptor-ligand interactions and signal transmission across membranes. Students find my lab fascinating
because of the wide range of techniques we use, including cell biological work on whole cells, determination of structures
of receptors and ligands, single-molecule work on receptor-ligand interactions, and biophysical studies of signal
transduction across the plasma membrane. Here are five areas that currently fascinate us.
How are conformational signals transmitted across membranes in integrins and the epidermal growth factor receptor
(EGFR)? Each have two transmembrane domains. Currently, there are many structures of extracellular domains in
unliganded/resting and liganded/active states, and cytoplasmic (e.g. kinase) domains in inactive and active states. However,
there is essentially no information about how activation of the extracellular domains causes activation of the kinase
domains. We are developing new methods for determining structures and probing conformational change in
transmembrane and juxtamembrane domains so we can understand signal transmission across membranes.
How do G proteins and kinases activate integrins (inside-out signaling) so they can bind to extracellular ligands and cytoskeletal
proteins, to coordinate adhesion and directional cell migration? How can integrin activation be confined to lamellipodia?
How is conformational change transduced in the extracellular domains of integrins, to mediate inside-out and outside-in
signaling?
How can integrins, depending on their activation state, mediate transient adhesion that supports rolling, or alternatively,
firm adhesion, in postcapillary venules?
How can adhesion molecules such as integrins and selectins resist substantial forces that should break receptor-ligand
noncovalent bonds? Does the fact that many adhesion receptors have high affinity conformations that are more extended
than the low affinity conformation along the cell attachment site – ligand binding site axis give them a mechanical
advantage in resisting force? Can we measure this using novel receptor-ligand constructs with laser tweezers or the atomic
force microscope? Does von Willebrand factor sense shear in the bloodstream and activate hemostasis because extension
reveals otherwise hidden receptor binding sites?
Finally, how can we make connections between basic research and disease? In the past, we have found inherited defects of
integrins in leukocyte adhesion deficiency, ICAM-1 as the cellular receptor for rhinovirus, and SDF-1 as the natural ligand
for the HIV coreceptor CXCR4. Our discoveries of LFA-1 and LFA-3 resulted in the drugs efalizumab (Raptiva, LFA-1
antibody, Genentech) and elefacept (Amevive, LFA-3-Fc fusion protein, Biogen). We are currently developing and
characterizing antibodies specific for the activated conformation of integrin I domains as therapeutics for autoimmune
disease. Furthermore, our work on integrins and EGFR has important implications for development and improvement of
therapeutics directed to these receptors.
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Papers & Publications:
- Carman CV, Springer TA. 2004. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167: 377-388.
- Xiao T, Takagi J, Wang J-h, Coller BS, Springer TA. 2004. Structural basis for allostery in integrins and binding of ligand-mimetic therapeutics to the platelet receptor for fibrinogen. Nature 432: 59-67.
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