Structure of Receptors and Growth Factors Involved in Vasculogenesis, Angiogenesis and Lymphomagenesis

The structurally different receptors involved in angiogenesis can be grouped into the vascular endothelial growth factor (VEGF) receptor family and Tie receptor family. In addition, VEGF receptors also associate with “co-receptors” such as aVb3 integrin, vascular endothelial (VE)-cadherin, and neuropilin-1 and -2 (NRP-1, -2). Ephrin-B ligands and their Eph receptors are involved in the differentiation of arteries and veins. The specificity of ligand binding to the receptors is indicated by the arrows above the receptors. The Tie receptor family has two members, Tie-1 and Tie-2. The extracellular region consists of two immunoglobulin (Ig)-like domains that are separated by three epidermal growth factor (EGF)-like cysteine repeats and are followed by three fibronectin type III homology domains. The VEGF receptor family consists of three transmembrane receptors, VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), and VEGFR-3 (Flt-4). A soluble form of VEGFR-1 has also been documented. VEGFR-1 and VEGF-R2 contain seven extracellular Ig-like homology domains, but in VEGFR-3, the fifth IG-like domain is cleaved into disulfide-linked subunits. NRP-1 binds to specific residues present in some VEGFs that bind to VEGFR-1 and VEGFR-2. aVb3 integrin and VE-cadherin have also been found in complexes with activated VEGFR-2. Both VEGF and Tie receptors contain two tyrosine kinase domains spaced by a kinase insert domain in the intracellular region of the receptor. These receptors can participate in various biological functions including cell survival, migration, differentiation, as well as vessel sprouting, stabilization, and permeability. Additionally, Eph receptors, with a total of 14 known receptors in mammals, constitute the largest subgroup in the receptor tyrosine kinase (RTK) family. They are able to bind to nine ephrin ligands, which unlike most RTK ligands, are membrane-bound cell surface molecules. There is very little crosstalk between the different subclasses of ephrins and Eph receptors, whereas binding within each subclass is highly promiscuous and leads to a large number of possible ligand-receptor interactions. Ephrin ligands are capable of receptor-like active signaling in addition to their ligand function, resulting in bidirectional signaling both into the ligand-expressing and receptor-expressing cells.

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