VEGFR1 localisation to the Golgi apparatus a novel mechanism regulating endothelial physiology (360G-Wellcome-089055_Z_09_Z)

Vascular endothelial growth factor A (VEGF-A) regulates new blood vessel formation, blood pressure control and disease states such as atherosclerosis, hypertension and tumour metastasis. The VEGFR1 (Flt-1) gene product is a receptor tyrosine kinase that binds to VEGF-A but its exact role in regulating vascular physiology remains unclear. We have discovered that VEGFR1 is localised to the Golgi apparatus and can be translocated to the plasma membrane upon elevation of cytosolic calcium ions. What is the mechanism underlying this phenomenon and how does this relate to the endothelial response to growth factors such as VEGF-A or placental growth factor (PlGF-1)? We will map VEGFR1 sequences that mediate Golgi localisation and utilise this information to manipulate VEGFR1 distribution to assess effects on endothelial signalling and migration. Proteomic and yeast-based analyses will be used to identify VEGFR1-specific interactions. Such gene products will be tested for ubiquitous and calciu m-sensitive interactions with VEGFR1. The roles of VEGFR1-associated proteins in regulating endothelial function will be determined using RNAi to assess their involvement in intracellular signalling, cell migration, cell proliferation and angiogenesis.