New variants of neuropilin-2 and their effects on progression and therapy resistance of malignant diseases
Neuropilin-2 is a non-tyrosine kinase membrane protein that serves as co-receptor for activating ligands of the vascular endothelial growth factor (VEGF) family in combination with the cognate VEGF receptors. In addition, inhibitory signals provided by soluble class 3 semaphorins are also bundled via neuropilin-2 and transmitted to signaling receptors of the plexin A group.
Two sister genes, neuropilin-1 and neuropilin-2, are conserved among jawed vertebrates with related signaling partners, but physiologically restricted to mostly non-overlapping expression domains in neuronal, endothelial, but also immune cell subpopulations.
Reference neuropilin-2 isoforms
Three major isoforms are transcribed from the neuropilin-2 gene in humans and translate into a soluble scavenger receptor for VEGF ligands (s9-NRP2) and two membrane-spanning forms with altered carboxyterminal domains (NRP2b and NRP2a). While signaling properties are well studied for NRP2a, the NRP2b isoform emerged recently as an inducible factor involved in cancer cell migration and metastasis formation.
Novel neuropilin-2 isoforms and variants
Apart from the known NRP2 isoforms, we are characterizing the impact of a novel NRP2b polymorphism on tumor initiation, progression and metastatic spread in prostate and urothelial carcinomas.
A novel splice variant of NRP2 is expressed in a variety of healthy and tumor tissues and might complement the regulatory function of the known s9-NRP2 scavenger receptor.
Analysis of genomic and expression data of primitive vertebrates reveals an abundance of neuropilin precursor genes with similar protein architecture, but also of precursors lacking the MAM domain involved in protein-protein interaction with possible implications for the functionality of the derived ancestral proteins.