The VEGF Molecular Signalling Pathway Mechanism Explained
By Amirali Banani
February 24, 2023
Vascular endothelial growth factor-A (VEGF-A) is essential for endothelial cell functions associated with angiogenesis (1). The signalling pathway begins with the binding of VEGF Receptors (VEGFR) to the VEGF cytokine to form a homodimer, a process known as Dimerization (2). The binding of a VEGF molecule to two VEGFR molecules induces the transphosphorylation of the intracellular domains of the receptors, leading to signal transduction (2, 3). In this section, we will be investigating the most prominent ligand-receptor complex in the VEGF System: VEGF-A/VEGFR2. VEGFR2, the major signal transducer for angiogenesis, is involved in the phospholipase C-γ-protein kinase C-mitogen-activated protein kinase (PLC-γ-PKC-MAPK) pathway, which is the pathway of interest that will be explained in this section (4). In this system, the VEGF-A molecule binds to and dimerizes VEGFR-1 and VEGFR-2, and signal transduction networks initiated by the VEGF-A/VEGFR2 complex promote angiogenesis, vascular permeability, as well as endothelial cell survival, migration, and proliferation (1,3,5). The dimerization of VEGFR-1 and VEGFR-2 as well as the transphosphorylation between the receptors’ intracellular kinase domains is followed by the activation of the VEGF Receptor Tyrosine Kinase (RTK) which induces the phosphorylation of an effector known as phospholipase C — gamma (PLC-γ) (5,6). After that, PLC-γ initiates a downstream intracellular signalling cascade that is facilitated by the sequential phosphorylation of a series of proteins called second messengers (6). The intracellular signal transduction process is regulated by several kinases of the MAPK pathway which phosphorylate and activate the downstream second messenger proteins, following the order: Ras-Raf-MEK-ERK (7,8). The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways and plays a paramount role in the survival and development of malignant tumour cells (7). In the last step of the PLC-γ-PKC-MAPK pathway, activated ERK 1/2 phosphorylates another kinase called RSK and both molecules travel to the nucleus of the vascular endothelial cell to activate multiple transcription factors which leads to effector protein synthesis, thus promoting cell proliferation and survival, and ultimately resulting in angiogenesis (9). Therefore, it can be observed through the PLC-γ-PKC-MAPK pathway that the hyperactivation of the expression of ERK 1/2 plays a crucial role in the development and progression of cancer through the promotion of rapid — and most of all aberrant — tumour neovascularization (10).
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