Our long term objective is to understand the mechanisms of regulation of the microtubule-dependent motor proteins, kinesin and cytoplasmic dynein. These motors drive the movement of cellular vesicles along microtubules within cells. Microtubule-dependent vesicle transport is an essential component of cellular membrane trafficking including endocytosis and exocytosis. Little is known about the mechanisms of regulation of kinesin and cytoplasmic dynein, or of the impact of modulation of their activity on cellular membrane trafficking. Numerous reports have documented the extensive rearrangement of cytoskeletal components (microtubules, microfilaments, and intermediate filaments) by okadaic acid, calyculin A, and microcystin-LR, members of a group of serine- threonine protein phosphatase inhibitors. Several groups have also reported that vesicle transport is inhibited by these toxins at doses that also elicit major cytoskeletal changes. Of considerable interest is our recent preliminary data on the ability of okadaic acid to stimulate vesicle motility at concentrations less than those which promote significant cytoskeletal changes, indicating that these toxins may elicit a concentration-dependent biphasic effect on vesicle transport. While okadaic acid and calyculin A are cell permanent, microcystin-LR is cell impermeant in all cell types except hepatocytes, which take-up this toxin via a membrane transporter. Using video- enhanced DIC microscopy, laser-scanning confocal microscopy, and protein phosphorylation studies, we will examine the regulation of microtubule- dependent vesicle transport by microcystin-LR in intact hepatocytes. Our hypothesis is that microcystin-LR, at doses less than those which perturb the cytoskeleton, can stimulate microtubule-dependent vesicle transport via protein phosphorylation of kinesin and cytoplasmic dynein.
Our specific aims are: 1. What is the effect of microcystin-LR on microtubule-dependent vesicle transport in intact hepatocytes. 2. Does microcystin-LR alter protein phosphorylation patterns of kinesin and cytoplasmic dynein.
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