Identification of two novel alternatively spliced Neuropilin-1 isoforms.
Neuropilin-1 (NRP1) is a coreceptor to a tyrosine kinase receptor for both the vascular endothelial growth factor (VEGF) family and semaphorin (Sema) family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion. NRP1 contains three distinct extracellular domains, a1a2, b1b2, and c. We report here the identification of two novel soluble human NRP1 isoforms, which we named sIIINRP1 and sIVNRP1. These soluble NRP1 isoforms were generated by alternative splicing of the NRP1 gene, a common regulatory mechanism occurring in cell surface receptor families. Both sIIINRP1 and sIVNRP1 contain a1a2 and b1b2 domains, but no c domain, and the rest of the NRP1 sequence. Additionally, sIIINRP1 is missing 48 amino acids within the C-terminus of the b2 domain. Both sIIINRP1 and sIVNRP1 are expressed in human cancerous and normal tissues. These molecules are capable of binding to VEGF165 and Sema3A. Furthermore, recombinant sIIINRP1 and sIVNRP1 proteins inhibit NRP1-mediated MDA-MB-231 breast cancer cell migration. These results indicate the multiple levels of regulation in NRP1 function and suggest that these two novel NRP1 isoforms are useful antagonists for NRP1-mediated cellular activities.
Cackowski
Frank C
FC
Cancer Institute and Department of Pathology, University of Pittsburgh, Research Pavilion at Hillman Cancer Center, Room 2.19, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, USA.
Xu
Li
L
Hu
Bo
B
Cheng
Shi-Yuan
SY
D017398:Alternative Splicing / Q000235:genetics*; D001369:Axons / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology; D039942:Neuropilin-1 / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D039961:Semaphorins / Q000378:metabolism
D020033:Protein Isoforms; D039961:Semaphorins; D039942:Neuropilin-1; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor