Neuropilins: structure, function and role in disease

Abstract

NRPs (neuropilins) are co-receptors for class 3 semaphorins, polypeptides with key roles in axonal guidance, and for members of the VEGF (vascular endothelial growth factor) family of angiogenic cytokines. They lack a defined signalling role, but are thought to mediate functional responses as a result of complex formation with other receptors, such as plexins in the case of semaphorins and VEGF receptors (e.g. VEGFR2). Mutant mouse studies show that NRP1 is essential for neuronal and cardiovascular development, whereas NRP2 has a more restricted role in neuronal patterning and lymphangiogenesis, but recent findings indicate that NRPs may have additional biological roles in other physiological and disease-related settings. In particular, NRPs are highly expressed in diverse tumour cell lines and human neoplasms and have been implicated in tumour growth and vascularization in vivo. However, despite the wealth of information regarding the probable biological roles of these molecules, many aspects of the regulation of cellular function via NRPs remain uncertain, and little is known concerning the molecular mechanisms through which NRPs mediate the functions of their various ligands in different cell types.

Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells

“…NRP1 overexpression in Panc-1 cells was found to reduce tumor volume and incidence, 31 and there is also evidence pointing to potentially differential or antagonistic roles of NRP1 and NRP2 in tumor cell regulation. 27 In agreement with murine studies, data from human surgical wounds indicate endothelial NRP1 upregulation early in the wound-healing process, that is, by 2 weeks after injury. 26 Thereafter, NRP1 expression is downregulated as tissue repair continues.…”

“…3,25,27 Overexpression of NRP1 has been shown to be positively associated with the metastatic potential, advanced stage, and clinical grade of prostate carcinoma. 28 NRP1 upregulation in gastrointestinal carcinomas seems to correlate with invasive behavior and metastatic potential.…”

“…[8][9][10] The cells (passages [20][21][22][23][24][25][26][27][28][29][30] were grown at 371C in a humidified 5% CO 2 atmosphere, and split at a 1:10 ratio, once a week. After growth to a subconfluent state, cells were washed once, made quiescent by incubation in serum-and supplementfree medium for 48 h, and then used for experiments.…”

Regulation of immune cell responses by semaphorins and their receptors

“…73 NP-1 is also expressed by various kinds of human tumor-cell lines and neoplasms. 74 Clinical studies suggest that NP-1 plays a role in tumor growth and disease progression due to mediating VEGF signals. 75,76 Recent studies have shown that semaphorins are secreted from tumor cells as well as macrophages and fibroblasts in the tumor microenvironment, thereby influencing cancers and their microenvironments.…”

Semaphorin and neuropilin expression during early morphogenesis of Xenopus laevis

“…In addition to interaction with plexins, semaphorin signaling can be further modulated by semaphorin co-receptors. Most of the vertebrate-secreted class-3 semaphorins do not directly interact with plexins, but bind to neuropilin co-receptors to activate plexins (Pellet-Many et al, 2008). This interaction is necessary for neural crest migration, since Nrp2 knockout, like the Sema3F knockout, disturbs the segmental neural crest migration pattern (Gammill et al, 2006(Gammill et al, , 2007 and since embryos lacking either Sema3A or Nrp1 show ectopic neural crest cells (Schwarz et al, 2008).…”