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(The FASEB Journal. 2007;21:1292)
© 2007 FASEB
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Binding of the C-terminal amino acids of VEGF121 directly with neuropilin-1 should be considered

Mathew A. von Wronski1, Michael F. Tweedle and Adrian D. Nunn

Bracco Research USA, Princeton, New Jersey, USA

1Correspondence: mvonwron{at}bru.bracco.com

Shraga-Heled et al. reported experimental results in The FASEB Journal indicating that the potency of VEGF121 is enhanced by the coexpression of neuropilin-1 (NP-1) with VEGFR-2 "... even though VEGF121 does not bind to neuropilins" (1) . Although the authors do not propose a specific mechanism for the phenomenon, they suggest that it may be dependant on spontaneously formed VEGFR-2/NP-1 complexes. We would like to point out an initial report that we coauthored (2) and two subsequent reports (3 , 4) indicating that the C-terminal peptide coded for by exon 8 in most isoforms of VEGF-A, including VEGF121, binds to neuropilin-1. Until the appearance of those reports, the conservation of exon 8 (coding for only 6 amino acids) in the various VEGF-A splice forms had been frequently noted but rarely commented on. Although the interaction between the six C-terminal amino acids of VEGF-A and NP-1 is relatively modest on its own (micromolar affinity), with VEGF tightly bound to VEGFR-2, even a weak interaction between the exon 8-encoded sequence and a nearby neuropilin-1 could have a significant impact on VEGF signaling. When the exon 8-encoded amino acids are replaced, as in the case of VEGF165b, an angiogenesis inhibitor is created that no longer binds to NP-1 (4) , indicating that the enhancement of VEGFR-2 signaling by NP-1 involves a direct interaction with the exon 8-encoded peptide.

We believe that the binding of the C-terminal amino acids of VEGF121 directly with neuropilin-1 should be considered when interpreting the results reported by Shraga-Heled et al. as it could possibly hasten productive lines of research in the area.

FOOTNOTES

The opinions expressed in editorials, essays, letters to the editor, and articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals@faseb.org.

REFERENCES

  1. Shraga-Heled, N., Kessler, O., Prahst, C., Kroll, J., Augustin, H., Neufeld, G. (2006) Neuropilin-1 and neuropilin-2 enhance VEGF121 stimulated signal transduction by the VEGFR-2 receptor. FASEB J. 21,915-926[CrossRef][Medline]
  2. von Wronski, M. A., Raju, N., Pillai, R., Bogdan, N. J., Marinelli, E. R., Nanjappan, P., Ramalingam, K., Arunachalam, T., Eaton, S., Linder, K. E., Yan, F., Pochon, S., Tweedle, M. F., Nunn, A. D. (2006) Tuftsin binds neuropilin-1 through a sequence similar to that encoded by exon 8 of vascular endothelial growth factor. J. Biol. Chem. 281,5702-5710[Abstract/Free Full Text]
  3. Jia, H., Bagherzadeh, A., Hartzoulakis, B., Jarvis, A., Lohr, M., Shaikh, S., Aqil, R., Cheng, L., Tickner, M., Esposito, D., Harris, R., Driscoll, P. C., Selwood, D. L., Zachary, I. C. (2006) characterization of a bicyclic peptide neuropilin-1 (NP-1) antagonist (EG3287) reveals importance of vascular endothelial growth factor exon 8 for NP-1 binding and role of NP-1 in KDR signaling. J. Biol. Chem. 281,13493-13502[Abstract/Free Full Text]
  4. Cebe Suarez, S., Pieren, M., Cariolato, L., Arn, S., Hoffmann, U., Bogucki, A., Manlius, C., Wood, J., Ballmer-Hofer, K. (2006) A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol. Life Sci. 63,2067-2077[CrossRef][Medline]

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