Kaori Yamada, PhD
Research Assistant Professor
Regulation of Cell Polarity.
PIP3 lipid trafficking by GAKIN/KIF13B, and its role in polarity determination
Cell polarity is a fundamental process required for the function of many cell types. Its misregulation frequently leads to developmental abnormalities and diseases such as cancer. The neuron is a highly polarized cell having multiple dendrites and only one axon. A key question arises: what determines this polarity? PIP3 has emerged as an essential cellular polarity-determining factor in cmany cell types, including neurons, epithelial cells, and migrating cells. Recently, we demonstrated that PIP3 is transported by a molecular motor-dependent trafficking mechanism. GAKIN/KIF13B, a kinesin-3 family protein, contributes the PIP3 vesicle trafficking along microtubules, and the transport of PIP3 is essential for the maintenance of the functional asymmetry of the neurons. Further understanding of the molecular mechanisms of cell polarity is likely to identify novel pharmacological targets of therapeutic importance for illusive neurodegenerative diseases as well as brain tumors.
Microtubule-stimulated ATPase activity of GAKIN, and its regulation by human Dlg tumor suppressor
Loss of cell-cell adhesion and cell polarity are the hallmarks of malignant cancer progression. Human disc-large (hDlg) is a scaffolding protein critical for the maintenance of cell polarity and adhesion. Proper transport of polarity determination factors is of fundamental importance in the regulation and maintenance of cellular polarity and tissue organization. GAKIN/KIF13B is a kinesin-3 family motor, which mediates intracellular transport of cell polarity determination factors, such as PIP3 and hDlg. An intriguingly question thus arises: how is the trafficking of GAKIN regulated? Recently, we discovered a novel switch mechanism that requires a specific conformation of hDlg to activate the auto-inhibitory form of GAKIN. These findings predict that the molecular regulation of GAKIN is of potential significance for the determination and maintenance of cell polarity in many cell types. Further characterization of the hDlg-GAKIN complex will identify novel therapeutic targets against diseases caused by the loss-of-polarity such as cancer and developmental abnormalities.
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