Unrestrained mammalian target of rapamycin complexes 1 and 2 increase expression of phosphatase and tensin homolog deleted on chromosome 10 to regulate phosphorylation of Akt kinase

Falguni Das, Nandini Ghosh-choudhury, Nirmalya Dey, Chandi Charan Mandal, Lenin Mahimainathan, Balakuntalam S Kasinath, Hanna E. Abboud, Goutam Ghosh-choudhury

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Abstract

Tuberous sclerosis complex 2 (TSC2) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function to block growth factor-induced mammalian target of rapamycin (mTOR) signaling and are mutated in autosomal dominant hamartoma syndromes. mTOR binds to a spectrum of common and different proteins to form TOR complex 1 (TORC1) and TORC2, which regulate cell growth, division, and metabolism. TSC2 deficiency induces constitutive activation of mTOR, leading to a state of insulin resistance due to a negative feedback regulation, resulting in reduced Akt phosphorylation. We have recently described an alternative mechanism showing that in TSC2 deficiency, enhanced PTEN expression contributes to reduced Akt phosphorylation. To explore the mechanism of PTEN regulation, we used rapamycin and constitutively active mTOR to show that TORC1 increases the expression of PTEN mRNA and protein. We found that in TSC2 -/- mouse embryonic fibroblasts expression of a kinase-dead mutant of mTOR, which inhibits both TORC1 and TORC2, decreases the expression of PTEN via transcriptional mechanism. Furthermore, kinase-deadmTORincreased and decreased phosphorylation of Akt at catalytic loop site Thr-308 and hydrophobic motif site Ser-473, respectively. Moreover, inhibition of deregulated TORC1 in TSC2-null mouse embryonic fibroblasts or in 293 cells by down-regulation of raptor decreased the levels of the transcription factor Hif1α and blocked PTEN expression, resulting in enhanced phosphorylation of Akt at Thr-308 and Ser-473. Finally, knockdown of rictor or mSin1 attenuated the expression of Hif1α, which decreased transcription of PTEN. These results unravel a previously unrecognized cell-autonomous function of TORC1 and TORC2 in the up-regulation of PTEN, which prevents phosphorylation of Akt and may shield against the development of malignancy in TSC patients.

Original languageEnglish (US)
Pages (from-to)3808-3822
Number of pages15
JournalJournal of Biological Chemistry
Volume287
Issue number6
DOIs
StatePublished - Feb 3 2012

Fingerprint

Chromosomes, Human, Pair 10
Phosphorylation
Sirolimus
Chromosomes
Tuberous Sclerosis
Phosphoric Monoester Hydrolases
Phosphotransferases
Fibroblasts
PTEN Phosphohydrolase
Raptors
Hamartoma
Cell growth
Transcription
Metabolism
Cell Division
Insulin Resistance
Tensins
mechanistic target of rapamycin complex 1
TOR complex 2
Catalytic Domain

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Unrestrained mammalian target of rapamycin complexes 1 and 2 increase expression of phosphatase and tensin homolog deleted on chromosome 10 to regulate phosphorylation of Akt kinase. / Das, Falguni; Ghosh-choudhury, Nandini; Dey, Nirmalya; Mandal, Chandi Charan; Mahimainathan, Lenin; Kasinath, Balakuntalam S; Abboud, Hanna E.; Ghosh-choudhury, Goutam.

In: Journal of Biological Chemistry, Vol. 287, No. 6, 03.02.2012, p. 3808-3822.

Research output: Contribution to journalArticle

Das, Falguni ; Ghosh-choudhury, Nandini ; Dey, Nirmalya ; Mandal, Chandi Charan ; Mahimainathan, Lenin ; Kasinath, Balakuntalam S ; Abboud, Hanna E. ; Ghosh-choudhury, Goutam. / Unrestrained mammalian target of rapamycin complexes 1 and 2 increase expression of phosphatase and tensin homolog deleted on chromosome 10 to regulate phosphorylation of Akt kinase. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 6. pp. 3808-3822.
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AU - Mandal, Chandi Charan

AU - Mahimainathan, Lenin

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AU - Abboud, Hanna E.

AU - Ghosh-choudhury, Goutam

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