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Jiang X, Yeung RS.
Cancer Res. 2006 May 15;66(10):5258-69
Regulation of microtubule-dependent protein transport by the
TSC2/mammalian target of rapamycin pathway.
Department of Surgery, University of Washington, Seattle,
Washington 98195, USA.
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.
PMID: 16707451
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