Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns

The Journal of Biological Chemistry
M JeltschK Alitalo

Abstract

Vascular endothelial growth factors (VEGFs) and their receptors play key roles in angiogenesis and lymphangiogenesis. VEGF activates VEGF receptor-1 (VEGFR-1) and VEGFR-2, whereas VEGF-C activates VEGFR-2 and VEGFR-3. We have created a library of VEGF/VEGF-C mosaic molecules that contains factors with novel receptor binding profiles, notably proteins binding to all three VEGF receptors ("super-VEGFs"). The analyzed super-VEGFs show both angiogenic and lymphangiogenic effects in vivo, although weaker than the parental molecules. The composition of the VEGFR-3 binding molecules and scanning mutagenesis revealed determinants of receptor binding and specificity. VEGFR-2 and VEGFR-3 showed striking differences in their requirements for VEGF-C binding; extracellular domain 2 of VEGFR-2 was sufficient, whereas in VEGFR-3, both domains 1 and 2 were necessary.

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Citations

Feb 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Veli-Matti LeppänenKari Alitalo
Jul 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Veli-Matti LeppänenKari Alitalo
May 31, 2007·The Journal of Experimental Medicine·Maria WirzeniusKari Alitalo
Jul 5, 2012·Cold Spring Harbor Perspectives in Medicine·Sina Koch, Lena Claesson-Welsh
Jan 25, 2013·International Journal of Molecular Sciences·Jui-Chieh ChenJen-Liang Su
Jun 30, 2011·The Biochemical Journal·Sina KochLena Claesson-Welsh
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Sep 19, 2009·Biochimica Et Biophysica Acta·Felix S GrünewaldKurt Ballmer-Hofer
Dec 4, 2014·Cytokine & Growth Factor Reviews·Marco Rusnati, Marco Presta
Dec 24, 2017·British Journal of Clinical Pharmacology·Nidal Al-HunitiJianguo Li
Feb 28, 2018·Frontiers in Bioengineering and Biotechnology·Khushbu RauniyarMichael Jeltsch
Dec 13, 2007·Journal of Molecular Recognition : JMR·Rebecca L Rich, David G Myszka
May 18, 2019·ELife·Sawan Kumar JhaMichael Jeltsch
Sep 1, 2017·Molecular and Clinical Oncology·Ling-Ling KongYi-Sheng Zhang
Jul 4, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Terhi KärpänenKari Alitalo

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