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Comment
. 2006 Apr 4;103(14):5247-8.
doi: 10.1073/pnas.0601352103. Epub 2006 Mar 27.

mTOR is out of control in polycystic kidney disease

Keith E Mostov  1
Affiliations
Comment

mTOR is out of control in polycystic kidney disease

Keith E Mostov. Proc Natl Acad Sci U S A. .
No abstract available

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Working model of the regulation of mTOR by PC1. Many aspects of this model still have to be worked out. It seems clear that mTOR is inactive in normal adult kidney epithelial cells because one cannot detect phospho-mTOR or phospho-S6-kinase (S6K) and because rapamycin has no apparent effect on normal kidneys. Because tuberin is believed to be the major negative regulator of mTOR, it is reasonable to assume that tuberin is responsible for repressing mTOR in kidney epithelial cells. How does tuberin achieve this repression? The interaction data suggest that a function of the PC1 tail may be to assemble a complex with tuberin and mTOR. However, the inhibitory effect of tuberin on mTOR is known to be indirect. Tuberin contains a GTPase-activating protein (GAP) domain that can lead to the inactivation of the small G protein Rheb. Rheb, in turn, binds to and is required for the Ser/Thr kinase activity of mTOR. This model would therefore predict that Rheb should be part of the PC1/tuberin/mTOR complex. This model has not been shown yet. Another open question is whether hamartin is part of the complex. The dimer between tuberin and hamartin is thought to be the active component that normally down-regulates mTOR via Rheb. In this model, the proximity between tuberin, Rheb, and mTOR that is induced by PC1 ensures that mTOR remains inactive. In ADPKD patients, however, PC1 is mutated. Therefore, according to this model, the tuberin–Rheb–mTOR complex does not form (or not as efficiently). Under these conditions, tuberin also may be subject to phosphorylation by kinases such as Akt or Erk, which destabilize the tuberin–hamartin complex.
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