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Sci Rep. 2015 Sep 28;5:14534. doi: 10.1038/srep14534.

PAK2 is an effector of TSC1/2 signaling independent of mTOR and a potential therapeutic target for Tuberous Sclerosis Complex.

Author information

1
Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
2
Center for Experimental and Molecular Medicine Academic Medical Center, University of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands.
3
Department of Neuroscience, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
4
Department of Neuropathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience University of Amsterdam, Amsterdam, The Netherlands.
5
Department of Clinical Genetics, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
6
SEIN-Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands.

Abstract

Tuberous sclerosis complex (TSC) is caused by inactivating mutations in either TSC1 or TSC2 and is characterized by uncontrolled mTORC1 activation. Drugs that reduce mTOR activity are only partially successful in the treatment of TSC, suggesting that mTOR-independent pathways play a role in disease development. Here, kinome profiles of wild-type and Tsc2(-/-) mouse embryonic fibroblasts (MEFs) were generated, revealing a prominent role for PAK2 in signal transduction downstream of TSC1/2. Further investigation showed that the effect of the TSC1/2 complex on PAK2 is mediated through RHEB, but is independent of mTOR and p21RAC. We also demonstrated that PAK2 over-activation is likely responsible for the migratory and cell cycle abnormalities observed in Tsc2(-/-) MEFs. Finally, we detected high levels of PAK2 activation in giant cells in the brains of TSC patients. These results show that PAK2 is a direct effector of TSC1-TSC2-RHEB signaling and a new target for rational drug therapy in TSC.

PMID:
26412398
PMCID:
PMC4585940
DOI:
10.1038/srep14534
[Indexed for MEDLINE]
Free PMC Article

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