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The Tyrosine Kinase Receptor RET Interacts in Vivo with Aryl Hydrocarbon Receptor-Interacting Protein to Alter Survivin Availability

Unità di Genetica Medica (M.V., D.F., I.K., G.R., E.B.), Policlinico Universitario S. Orsola-Malpighi, 40138 Bologna, Italy; Bio3/Bioinformatics and Molecular Genetics (Faculty of Biology) (D.D., R.B.), University of Freiburg, 79085 Freiburg, Germany; Center for Biochemistry and Molecular Cell Research (Faculty of Medicine) (R.B.), and Center for Systems Biology (ZBSA) and FRIAS, School of Life Sciences (LIFENET) (R.B.), Albert-Ludwigs-University Freiburg, D79104 Freiburg, Germany; Department of Histopathology (I.M.), Ospedale Infantile Regina Margherita, 10126 Torino, Italy; Department of Neurosurgery (A.M.), A.S.O. CTO-CRF-M.Adelaide, 10131 Torino, Italy; and Department of Pharmacology (R.R.), University of Bologna, 40126 Bologna, Italy

Address all correspondence and requests for reprints to: Giovanni Romeo, Unità di Genetica Medica Policlinico Universitario S. Orsola-Malpighi, 40138 Bologna, Italy. E-mail: romeo{at}eurogene.org.

Context: RET is a tyrosine kinase transmembrane receptor expressed in two main alternative isoforms: RET9 and RET51. RET transduces a positive signal leading to survival, differentiation, or migration in the presence of its ligand glial cell line-derived neurotrophic factor, whereas in its absence a proapoptotic fragment that initiates a negative signaling for apoptosis is generated. The signal transduction mechanisms leading to apoptosis are still unclear.

Objective: To shed light on the mechanisms of RET-induced apoptosis, we searched for novel interactors of RET51.

Design: The "split ubiquitin yeast two-hybrid system" was used with RET51 as bait against a human brain expression library.

Results: We identified aryl hydrocarbon receptor-interacting protein (AIP), a cochaperone recently found mutated in pituitary adenoma patients, as a novel interactor of RET. We showed that RET interacts specifically with AIP both in mammalian cell lines and in vivo in the pituitary gland, regardless of the presence of pituitary adenoma-specific mutations. AIP and RET genes were sequenced in 28 pituitary adenoma, but no relevant mutations were found. In addition, we identified the proapoptotic domain of RET as responsible for the interaction with AIP. Finally, we demonstrated that the AIP-RET interaction does not require RET kinase activity or kinase-dependent signal transduction and that it prevents the formation of the AIP-survivin complex.

Conclusions: The identification of the AIP-RET complex represents a starting point to study key cellular processes involved in RET-induced apoptosis.

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