Tuftsin binds neuropilin-1 through a sequence similar to that encoded by exon 8 of vascular endothelial growth factor.
Tuftsin, Thr-Lys-Pro-Arg (TKPR), is an immunostimulatory peptide with reported nervous system effects as well. We unexpectedly found that tuftsin and a higher affinity antagonist, TKPPR, bind selectively to neuropilin-1 and block vascular endothelial growth factor (VEGF) binding to that receptor. Dimeric and tetrameric forms of TKPPR had greatly increased affinity for neuropilin-1 based on competition binding experiments. On endothelial cells tetrameric TKPPR inhibited the VEGF(165)-induced autophosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) even though it did not directly inhibit VEGF binding to VEGFR-2. Homology between exon 8 of VEGF and TKPPR suggests that the sequence coded for by exon 8 may stabilize VEGF binding to neuropilin-1 to facilitate signaling through VEGFR-2. Given the overlap between processes involving neuropilin-1 and tuftsin, we propose that at least some of the previously reported effects of tuftsin are mediated through neuropilin-1.
von Wronski
Mathew A
MA
Ernst Felder Laboratories, Bracco Research USA, 305 College Road East, Princeton, NJ 08540, USA. mvonwron@bru.bracco.com
Raju
Natarajan
N
Pillai
Radhakrishna
R
Bogdan
Nancy J
NJ
Marinelli
Edmund R
ER
Nanjappan
Palaniappa
P
Ramalingam
Kondareddiar
K
Arunachalam
Thangavel
T
Eaton
Steve
S
Linder
Karen E
KE
Yan
Feng
F
Pochon
Sibylle
S
Tweedle
Michael F
MF
Nunn
Adrian D
AD
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005091:Exons; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism*; D045423:Microbubbles; D015394:Molecular Structure; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011869:Radioligand Assay; D015398:Signal Transduction / Q000502:physiology; D014405:Tuftsin / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D005456:Fluorescent Dyes; D007155:Immunologic Factors; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D014405:Tuftsin