Human Molecular Genetics Advance Access originally published online on January 18, 2007
Human Molecular Genetics 2007 16(5):529-536; doi:10.1093/hmg/ddl485
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Evidence for a molecular link between the tuberous sclerosis complex and the Crumbs complex
1 IDBML, CNRS UMR6216, Case 907, Faculté des Sciences de Luminy, 13288 Marseille cedex 09, France, 2 Inserm, U599, Centre de Recherche en Cancérologie de Marseille and 3 Institut Paoli-Calmettes, Marseille F-13009, France, 4 Univ Méditerranée, Marseille F-13007, France and 5 LGMSC, CNRS UMR 5201, Domaine Rockefeller, 8 Av Rockefeller, 68373 Lyon cedex 08, France
* To whom correspondence should be addressed. Tel: +33 491269741; Fax: +33 491269748; Email: lebivic{at}ibdm.univ-mrs.fr
Received October 18, 2006; Revised December 8, 2006; Accepted December 30, 2006
In human, mutations in tuberous sclerosis complex protein 1 or 2 (TSC1/2 or hamartin/tuberin) cause tuberous sclerosis characterized by the occurrence of multiple hamartomas. On the other hand, mutations in the Crumbs homolog-1 (CRB1) gene cause retinal degeneration diseases including Leber congenital amaurosis and retinitis pigmentosa type 12. Here we report, using a two-hybrid assay, a direct molecular interaction between TSC2 C-terminal part and PDZ 2 and 3 of PATJ, a scaffold member of the Crumbs 3 (CRB 3) complex in human intestinal epithelial cells, Caco2. TSC2 interacts not only with PATJ, but also with the whole CRB 3 complex by GST-pull down assays. In addition, TSC2 co-immunoprecipitates and co-localizes partially with PATJ at the level of the tight junctions. Furthermore, depletion of PATJ from Caco2 cells induces an increase in mammalian Target Of Rapamycin Complex 1 (mTORC1) activity, which is totally inhibited by rapamycin. In contrast, in the same cells, inhibition of phosphoinositol-3 kinase (PI-3K) by wortmannin does not abolish rpS6 phosphorylation. These functional data indicate that the Crumbs complex is a potential regulator of the mTORC1 pathway, cell metabolism and survival through a direct interaction with TSC1/2.
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