Signal transduction by VEGF receptor-1 wild type and mutant proteins |
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| Authors: | Ito N Huang K Claesson-Welsh L |
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| Institution: | 1. Medical School, University of Sheffield, UK;2. Genetics Department, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico;3. Neonatology Department, Hospital de la Mujer, Aguascalientes, Mexico;4. Sheffield Diagnostic Genetics Service, Sheffield Children''s NHS Foundation Trust, UK;5. Sheffield Clinical Genetics Service, Sheffield Children‘s NHS Foundation Trust, UK;6. Highly Specialised Severe, Complex & Atypical OI Service, Sheffield Children''s NHS Foundation Trust, UK;1. Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;2. Department of Neurology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;3. Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA;4. Physics and Astronomy, Vanderbilt University School of Medicine, Nashville, TN, USA;5. Neurology, Vanderbilt University School of Medicine, Nashville, TN, USA;6. Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA;1. Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihama, Yamashiro-cho, Tokushima 770-8514, Japan;2. Department of Cellular and Molecular Neuropathology, Juntendo University, School of Medicine, Hongo 2-1-1, Bunkyou-ku, Tokyo 113-8421, Japan;3. Department of Neuropathology, Institute of Brain Science, Hirosaki University, Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;4. Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan |
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| Abstract: | The role of the vascular endothelial growth factor receptor-1 (VEGFR-1) in endothelial cell function is unclear. We have previously identified four tyrosine phosphorylation sites in the C-terminal tail of this receptor. We now show that the wild type VEGFR-1 expressed in porcine aortic endothelial (PAE/VEGFR-1) cells was able to transduce signals for increased DNA synthesis and proliferation. Tyrosine phosphorylation of phospholipase Cgamma (PLCgamma), tyrosine phosphatase SHP-2, Crk, and extracellular regulated kinases 1 and 2 (Erk1/2) was registered in response to VEGF-A treatment of the PAE/VEGFR-1 cells. VEGFR-1 mutated at Y1213, Y1242, and Y1333 were constructed and expressed in PAE cells, to the same level as that of PAE/VEGFR-1 cells. The affinities of the wild type and mutated receptors for VEGF-A(165) binding were similar. The mutated VEGFR-1 Y1213F expressed in PAE cells was kinase inactive. PAE cells expressing the mutated VEGFR-1 Y1242F and Y1333F receptors mediated increased tyrosine phosphorylation of PLCgamma in response to VEGF-A stimulation. However, these two mutant VEGFR-1 failed to mediate increased mitogenesis and were unable to stimulate increased tyrosine phosphorylation of SHP-2, Crk, and Erk1/2, indicating that the mutations lead to a perturbation in VEGF-A-induced signal transduction. |
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