Angiogenesis, formation of new blood vessels from pre-existing vessels, is an important process for development and pathological conditions such as ischemic diseases and cancer. Vascular endothelial growth factor (VEGF) and the receptor VEGFR2 play important role in developmental and pathological angiogenesis. Polarized distribution of VEGFR2 facing the VEGF-secreting tissue is essential for effective angiogenesis. However, the molecular mechanisms by which VEGFR2 distributes in a polarized manner in endothelial cells are not well known. The proposed studies based on our extensive supporting data will address the central role of the kinesin-3 family protein KIF13B, a microtubules plus end motor, in regulating the polarized transport of VEGFR2 to the endothelial cell surface, specifically to the leading edge of migrating cells and filopodia of sprouting tip cells. We will test the hypotheses that (i) phosphorylation on KIF13B by protein kinase D (PKD) is an obligatory cue for the polarized transport of VEGFR2 by KIF13B; (ii) polarized localization of integrin ?1 is a landmark defining the final destination of VEGFR2 trafficking by KIF13B and a node for the interaction among integrin ?1, KIF13B and VEGFR2; (iii) interfering with KIF13B function or expression inhibits angiogenesis in vivo (iii) specific inhibition of VEGFR2 trafficking by peptides inhibitors derived from the KIF13B-VEGFR2 interface is a potential novel therapeutic strategy for angiogenesis- related diseases. These studies will systematically address the following Specific Aims: (1) investigate mechanisms of KIF13B-mediated VEGFR2-trafficking to endothelial cell surface required for angiogenesis; (2) determine the inhibitory actions of KIF13B-mediated VEGFR2 trafficking on angiogenesis disease models in vivo. We will exploit state of the art technologies including live cell imaging, expression of mutant constructs, gene transfer, and murine models of angiogenesis to accomplish the aims.
The focus of the work is on angiogenesis, in which the studies will establish the relevance of VEGFR2 trafficking by KIF13B, a molecular motor, in the pathophysiology of tumor angiogenesis. The work will design and test potential therapeutic peptide that by inhibiting KIF13B function prevents VEGFR2 trafficking and angiogenesis. Our studies will test the effectiveness of these novel peptides in vascular diseases associated with angiogenesis.
|Yamada, Kaori H; Kang, Hojin; Malik, Asrar B (2017) Antiangiogenic Therapeutic Potential of Peptides Derived from the Molecular Motor KIF13B that Transports VEGFR2 to Plasmalemma in Endothelial Cells. Am J Pathol 187:214-224|