Characterization of Neuropilin-1 Structural Features That Confer Binding to Semaphorin 3A and Vascular Endothelial Growth Factor 165

Abstract

Neuropilin-1 (Npn-1) is a receptor for both semaphorin 3A (Sema3A) and vascular endothelial growth factor 165 (VEGF 165 ). To understand the role Npn-1 plays as a receptor for these structurally and functionally unrelated ligands, we set out to identify structural features of Npn-1 that confer binding to Sema3A or VEGF 165 . We constructed Npn-1 variants containing deletions within the "a" A complex but ordered series of axon guidance decisions during development is critical for the establishment of nervous system structure and function (1). The vertebrate vascular network is similarly complex, with interconnecting conduits that extend throughout the body that are often in close anatomical proximity to nerve pathways (2). Recent evidence suggests that at least some of the same ligand-receptor systems coordinate development of both the nervous system and the cardiovascular system. For example, Eph receptors and their ligands, the ephrins, were first characterized as mediators of repulsive guidance events crucial for correct navigation of neuronal growth cones and migrating neural crest cells (3, 4). Their unexpected role in blood vessel formation was revealed when mutant mice that lacked either ephrin B2 or its cognate receptor EphB4 were shown to die during embryogenesis due to cardiovascular dysfunction (5, 6). Consistent with this observation, ephrin B2 and EphB4 were shown to have a reciprocal expression patterns in arterial and venous endothelial cells (6).Another example of a cell surface receptor whose function is required for development of both the cardiovascular and nervous systems is neuropilin-1 (Npn-1).

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

“…10 Thus, while Nrp-1 expression may be required for Sema3A and VEGF-mediated VP, it appears that Nrp-1 may differentially induce VP by distinct pathways in response to Sema3A or VEGF due to distinct binding sites for VEGF and Sema3A on Nrp-1. 32 Previous studies revealed that inhibition of the Src family kinases Src or Yes through genetic ablation or a pharmacological inhibitor blocked the VP in response to VEGF and protected mice from tissue damage after myocardial infarction or stroke. [12][13][14] To shed light on the mechanism by which Sema3A induces VP, mice were systemically treated with a Src inhibitor SKI-606 and then challenged with subcutaneous injection of Sema3A or VEGF.…”

VEGF-A121a binding to Neuropilins – A concept revisited

“…The EC domain consists of two CUB calcium-binding homology domains (a1 and a2), two coagulation factor V and VII homology domains (b1 and b2) and a MAM (meprin) domain (c) critical for receptor dimerization. The b1/b2 and a1/a2 domains mediate the high-affinity binding of NRPs to their ligands – the VEGFs and the class 3 semaphorins 62 . The NRP cytoplasmic domain has 40 residues and allows binding of the PDZ domain-containing protein GIPC1 (or synectin) 49 .…”

Adhesion or Plasmin Regulates Tyrosine Phosphorylation of a Novel Membrane Glycoprotein p80/gp140/CUB Domain-containing Protein 1 in Epithelia

“…The CUB designation originates from the original three proteins identified with the motif: complement subcomponents (C1r/C1s), embryonic sea urchin protein (Uegf), and bone morphogenic protein 1 (Bmp1). CUB domains are thought to play roles in adhesion proteins, such as the galectins, DMBT1 (23), sperm adhesin (22), and neuropilin (24), and proteases including Bmp1/C-proteinase, tolloid, and MASP (16). gp140/p80 is encoded by the CDCP1 gene, which is elevated in human lung and colon tumors.…”