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Molecular and Cellular Biology, September 2009, p. 4812-4830, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00352-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Alternative TrkAIII Splice Variant Targets the Centrosome and Promotes Genetic Instability {triangledown}

Antonietta Rosella Farina,1,{dagger} Antonella Tacconelli,1,{dagger} Lucia Cappabianca,1 Gesilia Cea,1 Sonia Panella,1 Antonella Chioda,1 Alessandra Romanelli,2 Carlo Pedone,2 Alberto Gulino,3 and Andrew Reay Mackay1*

Department of Experimental Medicine, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy,1 Department of Biological Science, University of Naples Federico II, Naples, Italy,2 Department of Experimental Medicine, University of Rome La Sapienza, Rome, and Neuromed Institute, 86077 Pozzilli, Italy3

Received 18 March 2009/ Returned for modification 9 April 2009/ Accepted 21 June 2009

The hypoxia-regulated alternative TrkAIII splice variant expressed by human neuroblastomas exhibits oncogenic potential, driven by in-frame exon 6 and 7 alternative splicing, leading to omission of the receptor extracellular immunoglobulin C1 domain and several N-glycosylation sites. Here, we show that the TrkAIII oncogene promotes genetic instability by interacting with and exhibiting catalytic activity at the centrosome. This function depends upon intracellular TrkAIII accumulation and spontaneous interphase-restricted activation, in cytoplasmic tyrosine kinase (tk) domain orientation, predominantly within structures that closely associate with the fully assembled endoplasmic reticulum intermediate compartment and Golgi network. This facilitates TrkAIII tk-mediated binding of {gamma}-tubulin, which is regulated by endogenous protein tyrosine phosphatases and geldanamycin-sensitive interaction with Hsp90, paving the way for TrkAIII recruitment to the centrosome. At the centrosome, TrkAIII differentially phosphorylates several centrosome-associated components, increases centrosome interaction with polo kinase 4, and decreases centrosome interaction with separase, the net results of which are centrosome amplification and increased genetic instability. The data characterize TrkAIII as a novel internal membrane-associated centrosome kinase, unveiling an important alternative mechanism to "classical" cell surface oncogenic receptor tk signaling through which stress-regulated alternative TrkAIII splicing influences the oncogenic process.

* Corresponding author. Mailing address: Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, Coppito 2, Via Vetoio, L'Aquila 67100, Italy. Phone: 390862433542. Fax: 390862433523. E-mail: andrewreay.mackay{at}univaq.it

{triangledown} Published ahead of print on 29 June 2009.

{dagger} The first two authors contributed equally to this article.

Molecular and Cellular Biology, September 2009, p. 4812-4830, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00352-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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