Function of members of the neuropilin family as essential pleiotropic cell surface receptors

Abstract

The neuropilin (Nrp) family consists of essential multifunctional vertebrate cell surface receptors. Nrps were initially characterized as receptors for class III Semaphorin (Sema3) family members, functioning in axon guidance. Nrps have also been shown to be critical for vascular endothelial growth factor-dependent angiogenesis. Intriguingly, recent data show that Nrp function in these seemingly divergent pathways is critically determined by ligand-mediated cross-talk, which underlies Nrp function in both physiological and pathological processes. In addition to functioning in these two pathways, Nrps have been shown to specifically function in a number of other fundamental signaling pathways as well. Multiple general mechanisms have been found to directly contribute to the pleiotropic function of Nrp. Here we review critical general features of Nrps that function as essential receptors integrating multiple molecular cues into diverse cellular signaling.

Figure 1

Nrp function is essential for Sema3 dependent axon guidance. Nrps specifically bind to Sema3 family members through a bivalent binding mechanism allowing both specific and high-affinity binding. Engagement and activation of Plexin family receptors activates signaling in both physiological axon guidance and pathological spinal cord injury. Structures of proteins or homologues with known structures were utilized including: Semaphorin N-terminus: PDB=1OLZ (140); Neuropilin N-terminal domains: PDB=2QQK (109); Plexin extracellular domain N-terminus: PDB=3OKT (141); Plexin intracellular domain: PDB=3IG3 (142).

Figure 2

Nrp function is essential for VEGF dependent angiogenesis. Nrps specifically bind to the C-terminal basic domain of VEGF family members. Cooperative binding of VEGF by VEGFR and Nrp activates the angiogenic cascade necessary for developmental and homeostatic angiogenesis and also pathological signaling associated with tumorigenesis and other types of aberrant signaling. Structures of proteins with known structures were utilized including: VEGF-A cystine knot domain: PDB=2VPF (143); VEGF-A basic domain: PDB=4DEQ (14); Neuropilin N-terminal domains: PDB=2QQK (109); VEGFR2 Ig-like domain 2–3: PDB=2X1X (144); VEGFR2 Ig-like domain 7: PDB=3KVQ (137); VEGFR2 intracellular domain: PDB=1VR2 (145).

Figure 3

Cross-talk between Nrp ligands allows coordinated regulation of neuronal and vascular tissues. Both neurons and endothelial cells express Nrp which can respond to either Sema3 or VEGF family guidance cues. Regulation of competitive Nrp binding between different ligands allows for an additional level of dominant control of Nrp function.

Figure 4

Nrp utilizes common mechanisms to regulate diverse signaling pathways. A) Specific high-affinity ligand binding initiates Nrp mediated signaling. B) Engagement and organization of an active signaling complex is accomplished through specific receptor-ligand and co-receptor contacts. C) Ligand-independent receptor association forms a pre-activated receptor complex poised for signaling. D) Nrp regulates dynamic trafficking of signaling complexes. E) Binding of intracellular PDZ-domain proteins, including GIPC, allow direct coupling between Nrp ligand binding and signaling functions. F) Direct engagement of integrins allows Nrp to couple molecular events with cellular cues.