Neuropilin 2 expression and function in melanocytes and melanoma
Rizzo, Salvatore A
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Neuropilin 2 (NRP2) is a transmembrane protein receptor originally discovered in neurons, and their precursors, neural crest cells (NCC), which are a transient, migratory precursor population derived from neural ectoderm. NRP2 serves as both a vascular endothelial growth factor (VEGF) co-receptor to initiate a pro-angiogenic signaling cascade and as a receptor for the class 3 semaphorin family molecules (primarily SEMA3F). Binding of SEMA3F induces a strong repulsive and antiangiogenic signal. NRP2 was discovered on melanocytes, which was a novel finding. NRP2-positive melanocytes were first identified in the hair follicles of Nrp2+/gfp transgenic mouse model. It is known that melanocytes reside in the bulb of the hair, where they provide pigment. Melanocyte stem cell populations are found in the bulge, a superficial structure also containing keratinocyte precursors. NRP2 has also been suggested as a potential biomarker in cases of malignant melanoma. The aim of this study was to elucidate the role of NRP2 three areas: in the growth and development of hair, in melanocytes, and in malignant melanoma. A greater understanding of the role of NRP2 in these locales may have significant clinical significance in disease states such as alopecia, vitiligo, and melanoma. It was discovered that Nrp2 expression was strongest within the bulge region of the hair follicle where melanocyte stem cells reside. Additionally, human and mouse primary melanocytes express NRP2, whereas keratinocytes do not. Neither melanocytes nor melanoma express VEGFR2, indicating NRP2 may be serving as a SEMA3F receptor. The NRP2 receptor was functional in melanocytes as treatment with SEMA3F inhibited migration of both melanocytes and melanoma cultured lines. Melanoma cells downregulate expression of SEMA3F and upregulate the expression of NRP2. In the patient samples analyzed, the expression of NRP2 correlated with disease progression.