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Human Molecular Genetics Advance Access published online on January 18, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddl485
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© The Author 2007. Published by Oxford University Press. All rights reserved

Evidence for a molecular link between the Tuberous Sclerosis complex and the Crumbs complex

Dominique Massey-Harroche1, Marie-Hélène Delgrossi1, Lydie Lane-Guermonprez1, Jean-Pierre Arsanto1, Jean-Paul Borg2,4,5, Marc Billaud3 and André Le Bivic1,*

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, Marseille, F-13009 France 3 LGMSC, CNRS UMR 5201, Domaine Rockefeller, 8 Av Rockefeller, 68373, Lyon cedex 08, France 4 Institut Paoli-Calmettes, Marseille, F-13009 France 5 Univ Méditerranée, F-13007, Marseille, France

* : to whom correspondence should be sent: e-mail: lebivic{at}ibdm.univ-mrs.fr tel: 33 491 26 97 41 Fax: 33 491 26 97 48

Received October 18, 2006; Revised December 8, 2006; Accepted December 30, 2006

In human, mutations in either 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 homologue-1 (CRB1) gene cause retinal degeneration diseases including Leber Congenital Amaurosis (LCA) and retinitis pigmentosa type 12 (RP12). 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 with the whole CRB 3 complex by GST-pull down assays. In addition, TSC2 co-immunoprecipitates and colocalizes partially with PATJ at the level of the tight junctions. Furthermore, depletion of PATJ from Caco2 cells induces an increase of mammalian Target Of Rapamycin Complex 1 (mTORC1) activity that 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 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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