Structural studies on vascular endothelial growth factors and their receptors

Receptor tyrosine kinases (RTKs) are critical regulators of cellular processes, such as proliferation, differentiation, survival and migration. RTKs are activated by ligand-induced dimerization but strategies for inducing dimerization are surprisingly diverse.

Vascular endothelial growth factor receptors (VEGFRs) are almost completely endothelial cell specific and among the major mediators of both angiogenesis and lymphangiogenesis in development and in disease. VEGFR-2 and VEGFR-3 are the main receptors transducing angiogenic and lymphangiogenic signaling, respectively. VEGFRs have an extracellular domain of seven immunoglobulin (Ig) homology domains, a single transmembrane helix and a cytoplasmic tyrosine kinase (TK) domain. For activation, VEGFRs utilize the N-terminal Ig-like domains 1-3 for ligand binding and the membrane-proximal domains D4-7 for dimerization.

Our structure of VEGF-C in complex with the VEGFR-2 ligand binding domains, for the first time, defined a full set of interactions in VEGFR ligand binding and determinants of VEGFR-2 ligand specificity (Leppänen et al., 2010). On the other hand, crystal structure of VEGF-D revealed the structural determinants of its receptor binding and specificity (Leppänen et al., 2011).

Recently, we provided the structural basis of VEGF-C binding to VEGFR-3 and defined a new mechanism in VEGFR dimerization and activation (Leppänen et al., 2013). Using receptor mutants, we show that homotypic interactions in D5 and D7 are essential for VEGFR-3 activation.  Based on our data, we suggest a general mechanism for VEGFR dimerization and activation: ligand binding facilitates homotypic interactions in D5 and D7, resulting in specific positioning of the transmembrane and intracellular kinase domains in active receptor dimers. Ligand induced D2-3 reorientation seem to be required for correct priming of the membrane-proximal domains. In another study we show that the distinct receptor-activating properties of VEGF-B and PlGF can be attributed to the differential binding of D2-3 of VEGFR-1 (Anisimov et al., 2013).

Selected publications

Leppänen V-M, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K and Alitalo K (2013). Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Natl Acad Sci U S A 110:12960-5.

Anisimov A, Leppänen V-M, Tvorogov D, Zarkada G, Jeltsch M, Holopainen T, Kaijalainen S and Alitalo K  (2013). The basis for the distinct biological activities of vascular endothelial growth factor receptor-1 ligands. Sci Signal. 6(282):ra52.

Leppänen V-M, Jeltsch M, Anisimov A, Tvorogov D, Kalkkinen N, Toivanen P, Ylä-Herttuala S, Ballmer-Hofer K and Alitalo K (2011). Structural determinants of vascular endothelial growth factor-D receptor binding and specificity. Blood 117:1507-15.

Leppänen V-M, Prota AE, Jeltsch M, Anisimov A, Kalkkinen N, Strandin T, Lankinen H, Goldman A, Ballmer-Hofer K and Alitalo K (2010). Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc Natl Acad Sci U S A 107:2425-30.

Contact

Veli-Matti Leppänen, Ph.D., Veli-Matti.Leppanen ( at ) Helsinki.fi
Kari Alitalo, Academy Professor, director of the Wihuri Research Institute, Kari.Alitalo (at) Helsinki.fi
Alitalo K in Pubmed ⊕ Opens in a new tab.

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Wihuri Research Institute

Biomedicum Helsinki
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Director: Kari Alitalo
 
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