Molecular basis of VEGFR1 autoinhibition at the plasma membrane

Manas Pratim Chakraborty, Diptatanu Das, Purav Mondal, Pragya Kaul, Soumi Bhattacharyya, Prosad Kumar Das and Rahul Das ()
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Manas Pratim Chakraborty: Indian Institute of Science Education and Research Kolkata, Mohanpur campus
Diptatanu Das: Indian Institute of Science Education and Research Kolkata, Mohanpur campus
Purav Mondal: Indian Institute of Science Education and Research Kolkata, Mohanpur campus
Pragya Kaul: Indian Institute of Science Education and Research Kolkata, Mohanpur campus
Soumi Bhattacharyya: Indian Institute of Science Education and Research Kolkata, Mohanpur campus
Prosad Kumar Das: Indian Institute of Science Education and Research Kolkata, Mohanpur campus
Rahul Das: Indian Institute of Science Education and Research Kolkata, Mohanpur campus

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events. The reason why VEGFR1 is regulated differently from other VEGFRs remains unknown. Here, we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an inefficient kinase. The juxtamembrane inhibition of VEGFR1 suppresses its basal phosphorylation even at high receptor concentrations and transiently stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce ligand-independent activation of VEGFR1 and sustain tyrosine phosphorylation.

Date: 2024
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DOI: 10.1038/s41467-024-45499-2

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