Yamada, K. H., Nakajima, Y., Geyer, M., Wary, K. K., Ushio-Fukai, M., Komarova, Y., and Malik, A. B., (2014) KIF13B Regulates Angiogenesis through Golgi-Plasma Membrane Trafficking of VEGFR2. J. Cell Sci Oct 15;127 (Pt 20):4518-30. PMCID: PMC4197089
Angiogenesis is a new formation of the blood vessels from pre-existing vessels. Angiogenic sprouting has many common traits with axon guidance. The tip of the sprouting endothelial cells has massive membrane extensions called filopodia, which is also seen in the elongating axon in the neurons. Both cells sense the gradient of the growth factors and migrate toward the growth factors. The difference is that the sprouting endothelial cells migrate as a group and one rapidly migrating cell is selected from the group to lead the migration (called "tip cell"), whereas neuronal axon/dendrite specification happens within the same cell.
What is the determining factor for selecting the tip cell?
The tip cell has an upregulated receptor for the growth factor for angiogenesis. The growth factor is VEGF, and the main receptor for VEGF is VEGFR2. Upregulated VEGFR2 induces expression of DLL4 in the tip cell, which induces expression of Notch in the neighboring cells (called “stalk cell”), which in turn suppresses the expression of VEGFR2 in the stalk cells. In short, high expression and activation of VEGFR2 is the key to become tip cell.
To receive VEGF from the environment, VEGFR2 needs to be exposed to the cell surface. But VEGFR2 is actively endocytosed and transported between the cell surface and intracellular membrane compartments such as endosomes and the Golgi apparatus, called "VEGFR2 trafficking".
What transports VEGFR2 to the cell surface?
Microtubules and actin filaments are cytoskeletons in the cells, like highway and local roads, respectively. Kinesins and dyneins are molecular motors that transport molecules on the microtubules for the long distance. Kinesins move from perinuclear region to the periphery region (antegrade way), whereas dyneins move from periphery to perinuclear region (retrograde way). So, what transports VEGFR2 to the cell surface? It can be one of the kinesins among more than 40 members of kinesin family.
By testing the effect of the knockdown of each kinesin, we found several kinesins whose function is critical for VEGF-induced migration of the endothelial cells, which includes KIF13B. Using KIF13B as a bait, we searched the binding proteins of KIF13B, then we found VEGFR2. In fact, KIF13B directly interacts with VEGFR2 and transports VEGFR2 to the cell surface.
This figure is showing the cell surface VEGFR2 (red) and nuclei (blue). Before stimulation VEGFR2 was localized at the surface to receive VEGF in both control endothelial cells and the cells where KIF13B was knocked down. After stimulation with VEGF, VEGFR2 was rapidly internalized (disappeared from the surface at 1 hour), and restored later to the surface (4 hour and 8 hours after stimulation). Knockdown of KIF13B inhibited the restoration of VEGFR2 to the cell surface.
Further studies revealed that the VEGFR2 trafficking mediated by KIF13B is necessary for VEGF-induced angiogenesis.
The VEGFR2 trafficking mediated by KIF13B can be a therapeutic target for angiogenesis-related diseases such as cancer and blinding eye diseases.
For the detail, please read the article.
Abbreviation
VEGF: vascular endothelial growth factor
VEGFR2: VEGF receptor 2
DLL4: delta like canonical Notch ligand 4
KIF13B: kinesin family 13B
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