TGF-β

TGF-β signaling regulates development, wound healing, immune responses, and tumour-cell growth and inhibition. Latent TGF-β and receptors for active TGF-β are ubiquitous; it is activation of TGF-β in the extracellular space that limits activity. Recently, we have determined a structure of latent TGF-β1 that reveals how the latency associated peptide (LAP), a 250 residue prodomain, shields the 110 residue growth factor and participates in its activation through interactions with αV integrins and latent TGF-β binding proteins (LTBPs). We also have studied how a different cell surface protein called GARP becomes disulfide linked to latent TGF-β, and presents it for activation by integrins αVβ6 and αVβ8 that are expressed on immune cells, and bind to an RGD motif in LAP. We believe that yet another cell surface molecule that presents latent TGF-β remains to be discovered. Furthermore, we are interested in understanding how other TGF-βs are activated, particularly TGF-β2, which lacks the RGD integrin-binding motif in its LAP sequence.  A wide range of projects, all the way from knockout mice to structure determination, are in the offing. 

Recent Publications

2017

Li, J. et al. Conformational equilibria and intrinsic affinities define integrin activation. EMBO J (2017) doi:10.15252/embj.201695803.
Li, J. et al. Conformational equilibria and intrinsic affinities define integrin activation. EMBO J (2017) doi:10.15252/embj.201695803.

2016

Nordenfelt, P., Elliott, H. & Springer, T. A. Coordinated integrin activation by actin-dependent force during T-cell migration. Nat Commun 7, 13119 (2016).
Nordenfelt, P., Elliott, H. & Springer, T. A. Coordinated integrin activation by actin-dependent force during T-cell migration. Nat Commun 7, 13119 (2016).
Su, Y. et al. Relating conformation to function in integrin α5β1. Proc Natl Acad Sci U S A. (2016).
Su, Y. et al. Relating conformation to function in integrin α5β1. Proc Natl Acad Sci U S A. (2016).

2015

Kim, J., Hudson, N. & Springer, T. Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases. Proc Natl Acad Sci USA 112, 4648–53 (2015).
Kim, J., Hudson, N. & Springer, T. Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases. Proc Natl Acad Sci USA 112, 4648–53 (2015).

2014

Springer. von Willebrand Factor, Jedi Knight of the Bloodstream. Blood 124, 1412–25 (2014).
Springer. von Willebrand Factor, Jedi Knight of the Bloodstream. Blood 124, 1412–25 (2014).
Dong, Hudson, Lu & Springer. Structural determinants of integrin β-subunit specificity for latent TGF-β. Nat Struct Mol Biol. 21, 1091–6 (2014).
Dong, Hudson, Lu & Springer. Structural determinants of integrin β-subunit specificity for latent TGF-β. Nat Struct Mol Biol. 21, 1091–6 (2014).
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