Abstract
Serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) has been implicated as a novel component of the mammalian target of rapamycin (mTOR) signaling pathway. Recently we have demonstrated that mTOR regulates cell motility in part through p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) pathways. Little is known about the role of PP2A in the mTOR-mediated cell motility. Here we show that rapamycin inhibited the basal or insulin-like growth factor 1 (IGF-1)-induced motility of human Ewing sarcoma (Rh1) and rhabdomyosarcoma (Rh30) cells. Treatment of the cells with rapamycin activated PP2A activity, and concurrently inhibited IGF-1 stimulated phosphorylation of Erk1/2. Inhibition of Erk1/2 with PD98059 did not significantly affect the basal mobility of the cells, but dramatically inhibited IGF-1-induced cell motility. Furthermore, inhibition of PP2A with okadaic acid significantly attenuated the inhibitory effect of rapamycin on IGF-1-stimulated phosphorylation of Erk1/2 as well as cell motility. Consistently, expression of dominant negative PP2A conferred resistance to IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. Expression of constitutively active MKK1 also attenuated rapamycin inhibition of IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. The results suggest that rapamycin inhibits cell motility, in part by targeting PP2A-Erk1/2 pathway.
Highlights
The mammalian target of rapamycin, a member of the phosphoinositide-39 kinase-related kinase family, is a central controller of cell proliferation, growth and survival [1]
Our previous studies have shown that rapamycin suppresses insulin-like growth factor 1 (IGF-1) stimulated motility in various tumor cell lines in part by inhibiting mTORC1-mediated 4E (eIF4E) binding protein 1 (4E-BP1) and S6 kinase 1 (S6K1) pathways [23]
We found that IGF-1 decreased the activity of phosphatase 2A (PP2A), which was prevented by rapamycin (Fig. 1B)
Summary
The mammalian target of rapamycin (mTOR), a member of the phosphoinositide-39 kinase-related kinase family, is a central controller of cell proliferation, growth and survival [1]. MTORC2 consists of mTOR, mLST8, mSin (mammalian stress-activated protein kinase-interacting protein 1), rictor (rapamycin insensitive companion of mTOR), and PRR5 (proline-rich protein 5), and is rapamycin-insensitive [9,10,11,12,13,14,15]. MTORC2 has been reported to phosphorylate SGK1 (serum and glucocorticoidinducible kinase 1) [17], this remains controversial [18]. Both mTORC1 and mTORC2 interact with a negative regulator DEPTOR [19]
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