title: Canonical and noncanonical vascular endothelial growth factor pathways: new developments in biology and signal transduction.
abstract: The past 5 years have witnessed a significant expansion in our understanding of vascular endothelial growth factor (VEGF) signaling. In particular, the process of canonical activation of VEGF receptor tyrosine kinases by homodimeric VEGF molecules has now been broadened by the realization that heterodimeric ligands and receptors are also active participants in the signaling process. Although heterodimer receptors were described 2 decades ago, their impact, along with the effect of additional cell surface partners and novel autocrine VEGF signaling pathways, are only now starting to be clarified. Furthermore, ligand-independent signaling (noncanonical) has been identified through galectin and gremlin binding and upon rise of intracellular levels of reactive oxygen species. Activation of the VEGF receptors in the absence of ligand holds immediate implications for therapeutic approaches that exclusively target VEGF. The present review provides a concise summary of the recent developments in both canonical and noncanonical VEGF signaling and places these findings in perspective to their potential clinical and biological ramifications.
authors.affiliation: From the Department of Molecular, Cell, and Developmental Biology (C.K.D., S.Z., M.L.I.-A.), Molecular Biology Institute (M.L.I.-A.), and Jonsson Comprehensive Cancer Center (M.L.I.-A.), University of California, Los Angeles.
authors.forename: Courtney K
authors.initials: CK
authors.lastname: Domigan
authors.affiliation: From the Department of Molecular, Cell, and Developmental Biology (C.K.D., S.Z., M.L.I.-A.), Molecular Biology Institute (M.L.I.-A.), and Jonsson Comprehensive Cancer Center (M.L.I.-A.), University of California, Los Angeles.
authors.forename: Safiyyah
authors.initials: S
authors.lastname: Ziyad
authors.affiliation: From the Department of Molecular, Cell, and Developmental Biology (C.K.D., S.Z., M.L.I.-A.), Molecular Biology Institute (M.L.I.-A.), and Jonsson Comprehensive Cancer Center (M.L.I.-A.), University of California, Los Angeles. arispe@mcdb.ucla.edu.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
mesh_terms: D043924:Angiogenesis Modulating Agents / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication; D037161:Galectins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011487:Protein Conformation; D055503:Protein Multimerization; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D043924:Angiogenesis Modulating Agents; C486399:GREM1 protein, human; D037161:Galectins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: endothelial cells