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Neuropilin‐1 and neuropilin‐2 enhance VEGF 121 stimulated signal transduction by the VEGFR‐2 receptor
Author(s) -
ShragaHeled Niva,
Kessler Ofra,
Prahst Claudia,
Kroll Jens,
Augustin Hellmut,
Neufeld Gera
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6277com
Subject(s) - neuropilin 1 , phosphorylation , chemistry , neuropilin , tyrosine phosphorylation , receptor , signal transduction , microbiology and biotechnology , vegf receptors , vascular endothelial growth factor , biology , biochemistry , cancer research
The neuropilin‐1 (np1) receptor binds the 165 amino‐acid form of vascular endothelial growth factor 165 (VEGF 165 ) and functions as an enhancer that potentiates VEGF 165 signaling via the VEGFR‐2 ty‐rosine‐kinase receptor. To study the mechanism by which neuropilins potentiate VEGF activity we produced a VEGF 165 mutant (VEGF 165KF ) that binds to neuropilins but displays a much lower affinity toward VEGFR‐1 and VEGFR‐2. VEGF 165KF failed to induce VEGFR‐2 phosphorylation in cells lacking neuropilins. However, in the presence of np1, VEGF 165KF bound weakly to VEGFR‐2, induced VEGFR‐2 phosphorylation, and activated ERK1/2. Interestingly, VEGF 165KF did not promote formation of VEGFR‐2/np1 complexes nor did high concentrations of VEGF 165KF inhibit VEGF 165 induced formation of such complexes, suggesting that VEGF 165 does not stabilize VEGFR‐2/ np1 complexes by forming bridges spanning VEGFR‐2 and np1. VEGF 121 is a VEGF form that does not bind to neuropilins. Surprisingly, both np1 and neuropilin‐2 (np2) enhanced VEGF 121 ‐induced phosphorylation of VEGFR‐2 and VEGF 121 ‐induced proliferation of endo‐thelial cells. The enhancement of VEGF 121 activity by np1 was accompanied by a 10‐fold increase in binding affinity to VEGFR‐2 and was not associated with the formation of new VEGFR‐2/np1 complexes. These observations suggest that neuropilins enhance the activity of VEGF forms that do not bind to neuropilins, indicate that np2 is a functional VEGF receptor, and imply that spontaneously formed VEGFR‐2/np1 complexes suffice for efficient neuropilin mediated enhancement of VEGF activity.—Shraga‐Heled, N., Kessler, O., Prahst, C., Kroll, J., Augustin, H., Neufeld, G. Neuropilin‐1 and neuropilin‐2 enhance VEGF 121 stimulated signal transduction by the VEGFR‐2 receptor. FASEB J. 21, 915–926 (2007)