Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway.

Abstract	Protein transport plays a critical role in the interaction of the cell with its environment. Recent studies have identified TSC1 and TSC2, 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. Tsc1- and Tsc2-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 Tsc2-/- cells. Together, these findings highlight a novel role of the TSC2/mTOR pathway in regulating microtubule-dependent protein transport.
Authors	Xiuyun Jiang, Raymond S Yeung
Journal	Cancer research (Cancer Res) Vol. 66 Issue 10 Pg. 5258-69 (May 15 2006) ISSN: 0008-5472 [Print] United States
PMID	16707451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Caveolin 1 Microtubule-Associated Proteins Neoplasm Proteins Tsc2 protein, mouse Tsc2 protein, rat Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins cytoplasmic linker protein 170 Protein Kinases mTOR protein, mouse TOR Serine-Threonine Kinases
Topics	Animals Caveolin 1 (metabolism) Cells, Cultured Down-Regulation Mice Microtubule-Associated Proteins (metabolism) Microtubules (metabolism) Neoplasm Proteins (metabolism) Protein Kinases (metabolism) Protein Transport (drug effects, physiology) Rats Signal Transduction TOR Serine-Threonine Kinases Transfection Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins (genetics, metabolism)

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