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.
Highlights
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway has been implicated in many sporadic human cancers, including prostate, breast, endometrium, glioma, etc. [1]
Caveolin-1 is a structural protein of caveolae, which normally localizes to specialized microdomains of the plasma membrane known as lipid rafts, but in Tsc2À/À (EEF-8) rat embryonic fibroblasts (REF) most of the caveolin-1 resided in punctate cytoplasmic vesicles (Fig. 1A, top row, left) as described previously [21]
A second independently derived Tsc2À/À cell line (EEF-4A) from the Eker rat and a Tsc1À/À mouse embryonic fibroblasts (MEF) cell line (Fig. 1A, bottom row) were tested under identical conditions, and the results showed the same effects on caveolin-1 localization
Summary
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway has been implicated in many sporadic human cancers, including prostate, breast, endometrium, glioma, etc. [1]. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway has been implicated in many sporadic human cancers, including prostate, breast, endometrium, glioma, etc. MTOR activation is a common phenomenon observed in tumors arising from several hereditary syndromes, including Cowden’s disease, tuberous sclerosis, PeutzJeghers syndrome, and neurofibromatosis 1 [2]. The underlying genetic defects of these syndromes involve the PTEN, TSC1 and TSC2, LKB1, and NF1 tumor suppressor genes, respectively, whose biochemical functions are at least partially linked to the regulation of mTOR activity. The pathologic features of the lesions associated with these tumor-predisposing syndromes illustrate abnormalities in cell growth, proliferation, differentiation, and migration, suggesting a function of mTOR signaling in mediating these biological processes. Recent investigations of the TSC1/TSC2 tumor suppressor genes have uncovered their connections to the mTOR pathway Serving as a GTPase-activating protein (GAP), the TSC1/ TSC2 heterodimer promotes hydrolysis of Rheb-GTP, a member of
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