Regulation of the cell function via trafficking of signaling molecules

The important question in my research is how cellular function is dynamically regulated by local activation of cell signaling. To induce the signaling locally, the signaling molecules need to be accumulated at the particular area of the cells. The accumulation of the molecules is mediated by the intracellular trafficking by the molecular motors; kinesins, dyneins, and myosins. Among them, we are particularly interested in the kinesin family protein, KIF13B, as it transports important signaling molecules, such as VEGFR2.

Trafficking of VEGFR2 by KIF13B is critical for angiogenesis, the formation of the new blood vessels from pre-existing vessels. Angiogenesis is a hallmark of cancer and blinding eye diseases such as wet age-related macular degeneration (wet AMD) and diabetic retinopathy. Pathogenic angiogenesis is induced by an excess amount of vascular endothelial growth factor (VEGF) in the diseased tissue. To response to VEGF, VEGFR2 needs to be exposed at the cell surface of endothelial cells. We found that the trafficking of VEGFR2 to the cell surface is mediated by a kinesin motor KIF13B. Based on the finding, we developed a small peptide inhibitor disrupting the interaction between VEGFR2 and KIF13B, thus inhibiting VEGFR2 trafficking. This peptide inhibitor successfully inhibited pathological angiogenesis in wet AMD and cancer.

Our projects focus on understanding the role of intracellular trafficking in the cell function, particularly dynamic cell sprouting in angiogenesis. Using live cell imaging of VEGFR2 in sprouting angiogenesis, we will tackle the interesting questions; how the trafficking is regulated, how the direction of the trafficking is decided, and what happens if the trafficking is activated or blocked. Moreover, using the mouse models of endothelial-specific KIF13B knockout and the aforementioned pharmacological inhibitor in disease models, such as cancer models, wet AMD models, and diabetic retinopathy models, we will address the role of the trafficking in progression of diseases, and whether we can develop the strategy to regulate the trafficking to inhibit pathological angiogenesis in these diseases.