Tyrosine phosphorylation of the scaffold protein IQGAP1 by VEGFR2 modulates cell proliferation
- 1Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland, USA
- 2Discovery Analytical, GlaxoSmithKline, Collegeville, Pennsylvania, USA
Abstract
IQGAP1 (IQ motif-containing GTPase activating protein 1), a scaffold protein with >250 interacting partners, regulates several intracellular signaling cascades, thereby modulating cell functions. Post-translational modifications of IQGAP1 by ubiquitination or phosphorylation have been shown to alter its interactions with selected proteins. We previously demonstrated that phosphorylation of Tyr-1510 of IQGAP1 by the MET receptor tyrosine kinase creates a docking site for Src homology 2 (SH2) domains of Abl. The vascular endothelial growth factor receptor 2 (VEGFR2) orchestrates angiogenesis by promoting endothelial cell survival, proliferation, and migration. Here, we show that the VEGFR2 kinase stimulates tyrosine phosphorylation of IQGAP1 in vitro and in cells; the latter is independent of SRC. Analysis by LC-MS/MS identifies Tyr-855 as the predominant site of IQGAP1 phosphorylation. Using a microarray screen, we identified that the SH2 domains of seven proteins bind to a peptide containing Tyr-855 of IQGAP1 in a phosphorylation-dependent manner. To assess the functional effects of Tyr-855 phosphorylation, we replaced Tyr-855 of IQGAP1 with alanine (IQGAP1 Y855A). The ability of VEGF to activate Akt and ERK and increase cell proliferation is abrogated when IQGAP1-null cells are reconstituted with IQGAP1 Y855A, indicating that phosphorylation of Tyr-855 of IQGAP1 modulates the ability of VEGF to activate at least some signaling pathways and promote cell proliferation. Taken together, our data suggest that IQGAP1 phosphorylation is a potential therapeutic target for neoplasms and other disorders characterized by increased VEGFR2 signaling.
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BibTeX
@article{sait2026tyrosine,
title = {{Tyrosine phosphorylation of the scaffold protein IQGAP1 by VEGFR2 modulates cell proliferation}},
author = {Mohammed Rizwan Babu Sait and Zhigang Li and Louise Thines and Tao Wang and Francesca Zappacosta and Roland S. Annan and David B. Sacks},
journal = {The Journal of Biological Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.jbc.2026.113593},
url = {https://doi.org/10.1016/j.jbc.2026.113593},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Tyrosine phosphorylation of the scaffold protein IQGAP1 by VEGFR2 modulates cell proliferation
AU - Mohammed Rizwan Babu Sait
AU - Zhigang Li
AU - Louise Thines
AU - Tao Wang
AU - Francesca Zappacosta
AU - Roland S. Annan
AU - David B. Sacks
PY - 2026
DA - 2026/09/23
JO - The Journal of Biological Chemistry
DO - 10.1016/j.jbc.2026.113593
UR - https://doi.org/10.1016/j.jbc.2026.113593
AB - IQGAP1 (IQ motif-containing GTPase activating protein 1), a scaffold protein with >250 interacting partners, regulates several intracellular signaling cascades, thereby modulating cell functions. Post-translational modifications of IQGAP1 by ubiquitination or phosphorylation have been shown to alter its interactions with selected proteins. We previously demonstrated that phosphorylation of Tyr-1510 of IQGAP1 by the MET receptor tyrosine kinase creates a docking site for Src homology 2 (SH2) domains of Abl. The vascular endothelial growth factor receptor 2 (VEGFR2) orchestrates angiogenesis by promoting endothelial cell survival, proliferation, and migration. Here, we show that the VEGFR2 kinase stimulates tyrosine phosphorylation of IQGAP1 in vitro and in cells; the latter is independent of SRC. Analysis by LC-MS/MS identifies Tyr-855 as the predominant site of IQGAP1 phosphorylation. Using a microarray screen, we identified that the SH2 domains of seven proteins bind to a peptide containing Tyr-855 of IQGAP1 in a phosphorylation-dependent manner. To assess the functional effects of Tyr-855 phosphorylation, we replaced Tyr-855 of IQGAP1 with alanine (IQGAP1 Y855A). The ability of VEGF to activate Akt and ERK and increase cell proliferation is abrogated when IQGAP1-null cells are reconstituted with IQGAP1 Y855A, indicating that phosphorylation of Tyr-855 of IQGAP1 modulates the ability of VEGF to activate at least some signaling pathways and promote cell proliferation. Taken together, our data suggest that IQGAP1 phosphorylation is a potential therapeutic target for neoplasms and other disorders characterized by increased VEGFR2 signaling.
SN - 0021-9258
SN - 1083-351X
ER -