title: PAK2 is an effector of TSC1/2 signaling independent of mTOR and a potential therapeutic target for Tuberous Sclerosis Complex.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Alves
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Gwenny M
authors.initials: GM
authors.lastname: Fuhler
authors.affiliation: Center for Experimental and Molecular Medicine Academic Medical Center, University of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands.
authors.forename: Karla C S
authors.initials: KC
authors.lastname: Queiroz
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Jetse
authors.initials: J
authors.lastname: Scholma
authors.affiliation: Department of Neuroscience, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: Goorden
authors.affiliation: Department of Neuropathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Anink
authors.affiliation: Center for Experimental and Molecular Medicine Academic Medical Center, University of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands.
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Bruno
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.affiliation: Department of Neuroscience, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Ype
authors.initials: Y
authors.lastname: Elgersma
authors.affiliation: Department of Neuropathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience University of Amsterdam, Amsterdam, The Netherlands.|SEIN-Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University of Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D058570:TOR Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins