Data from Regulation of Microtubule-Dependent Protein Transport by the TSC2/Mammalian Target of Rapamycin Pathway

Abstract

<div>Abstract<p>Protein transport plays a critical role in the interaction of the cell with its environment. Recent studies have identified <i>TSC1</i> and <i>TSC2</i>, two tumor suppressor genes involved in tuberous sclerosis complex, as regulators of the mammalian target of rapamycin (mTOR) pathway. Cells deficient in TSC1 or TSC2 possess high levels of Rheb-GTP resulting in constitutive mTOR activation. We have shown previously that the TSC1/TSC2 complex is involved in post-Golgi transport of VSVG and caveolin-1 in mammalian cells. Here, we show that modulation of mTOR activity affects caveolin-1 localization and that this effect is independent of p70S6K. <i>Tsc1</i>- and <i>Tsc2</i>-null cells exhibit abnormal caveolin-1 localization that is accompanied by disorganized microtubules in the subcortical region. Analyses of green fluorescent protein-EB1 and tubulin in live mutant cells suggest a failure of the plus-ends to sense cortical signals and to halt microtubule growth. Down-regulation of CLIP-170, a putative mTOR substrate with microtubule-binding properties, rescued the abnormal microtubule arrangement and caveolin-1 localization in <i>Tsc2</i>−/− cells. Together, these findings highlight a novel role of the TSC2/mTOR pathway in regulating microtubule-dependent protein transport. (Cancer Res 2006; 66(10): 5258-69)</p></div>