Modulation of Receptor Tyrosine Kinase Activity through Alternative Splicing of Ligands and Receptors in the VEGF-A/VEGFR Axis

Abstract

Vascular endothelial growth factor A (VEGF-A) signaling is essential for physiological and pathological angiogenesis. Alternative splicing of the VEGF-A pre-mRNA gives rise to a pro-angiogenic family of isoforms with a differing number of amino acids (VEGF-Axxxa), as well as a family of isoforms with anti-angiogenic properties (VEGF-Axxxb). The biological functions of VEGF-A proteins are mediated by a family of cognate protein tyrosine kinase receptors, known as the VEGF receptors (VEGFRs). VEGF-A binds to both VEGFR-1, largely suggested to function as a decoy receptor, and VEGFR-2, the predominant signaling receptor. Both VEGFR-1 and VEGFR-2 can also be alternatively spliced to generate soluble isoforms (sVEGFR-1/sVEGFR-2). The disruption of the splicing of just one of these genes can result in changes to the entire VEGF-A/VEGFR signaling axis, such as the increase in VEGF-A165a relative to VEGF-A165b resulting in increased VEGFR-2 signaling and aberrant angiogenesis in cancer. Research into this signaling axis has recently focused on manipulating the splicing of these genes as a potential therapeutic avenue in disease. Therefore, further research into understanding the mechanisms by which the splicing of VEGF-A/VEGFR-1/VEGFR-2 is regulated will help in the development of drugs aimed at manipulating splicing or inhibiting specific splice isoforms in a therapeutic manner.

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

“…Neuropilin 2 (NRP2), a cell surface transmembrane protein, was originally characterized as a receptor for type 3 semaphorins (such as SEMA3) and as a co-receptor of VEGFR2 [ 6 ]. NRP2 is primarily expressed in the nervous and vascular systems and is important for the development of embryos by enhancing VEGF-VEGFR binding [ 6 ]. Recent studies have reported that the neuropilin family is involved in tumor metastasis and is correlated with poor prognosis [ 7 , 8 ].…”

Soya-cerebroside inhibits VEGF-facilitated angiogenesis in endothelial progenitor cells

“…It is well established that VEGF facilitates aberrant tumour angiogenesis in vitro (Stevens & Oltean, 2019). We examined whether VEGF promotes EPC angiogenesis in vivo.…”

Overview of current targeted therapy in gallbladder cancer

“…VEGF/VEGFR VEGF/VEGFR axis plays a key role in both physiological and pathological vascularization in diseases such as tumor angiogenesis. [68][69][70][71] There are five distinct VEGF family members in a mammal: VEGF-A (also referred to as VEGF), VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PLGF). VEGFR family consists of RTK member, including VEGFR1, VEGFR2, and VEGFR3, as well as the non-tyrosine kinase co-receptors neuropilin-1 (NP-1) and NP-2.…”