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A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2

Cébe Suarez, S. ; Pieren, M. ; Cariolato, L. ; Arn, S. ; Hoffmann, U. ; Bogucki, A. ; Manlius, C. ; Wood, J. ; Ballmer-Hofer, K.

In: Cellular and Molecular Life Sciences CMLS, 2006, vol. 63, no. 17, p. 2067-2077

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    Title
    • A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2
    Author
    • Cébe Suarez, S.. Laboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, 5232, Villigen, PSI, Switzerland
    • Pieren, M.. Laboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, 5232, Villigen, PSI, Switzerland
    • Cariolato, L.. Laboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, 5232, Villigen, PSI, Switzerland
    • Arn, S.. Laboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, 5232, Villigen, PSI, Switzerland
    • Hoffmann, U.. Laboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, 5232, Villigen, PSI, Switzerland
    • Bogucki, A.. Friedrich Miescher Institute, Maulbeerstr. 66, 4058, Basel, Switzerland
    • Manlius, C.. Novartis Pharma Ltd, 4057, Basel, Switzerland
    • Wood, J.. Novartis Pharma Ltd, 4057, Basel, Switzerland
    • Ballmer-Hofer, K.. Laboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, 5232, Villigen, PSI, Switzerland
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Cellular and Molecular Life Sciences CMLS, 2006, vol. 63, no. 17, p. 2067-2077. Birkhäuser-Verlag; http://www.birkhauser.ch
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:309822
    Summary
    Abstract.: The development of functional blood and lymphatic vessels requires spatio-temporal coordination of the production and release of growth factors such as vascular endothelial growth factors (VEGFs). VEGF family proteins are produced in multiple isoforms with distinct biological properties and bind to three types of VEGF receptors. A VEGF-A splice variant, VEGF-A165b, has recently been isolated from kidney epithelial cells. This variant is identical to VEGF-A165 except for the last six amino acids encoded by an alternative exon. VEGF-A165b and VEGF-A165 bind VEGF receptors 1 and 2 with similar affinity. VEGF-A165b elicits drastically reduced activity in angiogenesis assays and even counteracts signaling by VEGF-A165. VEGF-A165b weakly binds to heparan sulfate and does not interact with neuropilin-1, a coreceptor for VEGF receptor 2. To determine the molecular basis for altered signaling by VEGF-A165b we measured VEGF receptor 2 and ERK kinase activity in endothelial cells in culture. VEGF-A165 induced strong and sustained activation of VEGF receptor 2 and ERK-1 and −2, while activation by VEGF-A165b was only weak and transient. Taken together these data show that VEGF-A165b has attenuated signaling potential through VEGF receptor 2 defining this new member of the VEGF family as a partial receptor agonist