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Molecular and Cellular Biology, October 2002, p. 7351-7363, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7351-7363.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Neuron-Specific Rai (ShcC) Adaptor Protein Inhibits Apoptosis by Coupling Ret to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway

Giuliana Pelicci,¹ Flavia Troglio,¹ Alessandra Bodini,¹ Rosa Marina Melillo,² Valentina Pettirossi,^1, Laura Coda,¹ Antonio De Giuseppe,³ Massimo Santoro,² and Pier Giuseppe Pelicci^1,4,5*

Department of Experimental Oncology, European Institute of Oncology, 20141 Milan,¹ Dipartimento di Biologia e Patologia Cellulare e Molecolare, Centro di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples,² Istituto di Medicina Interna e Scienze Oncologiche, Perugia University, 06100 Perugia,³ FIRC Institute for Molecular Oncology (IFOM), 20139 Milan,⁴ Università Vita-Salute San Rassaele, Milan, Italy⁵

Received 26 December 2001/ Returned for modification 8 February 2002/ Accepted 22 July 2002

Rai is a recently identified member of the family of Shc-like proteins, which are cytoplasmic signal transducers characterized by the unique PTB-CH1-SH2 modular organization. Rai expression is restricted to neuronal cells and regulates in vivo the number of postmitotic sympathetic neurons. We report here that Rai is not a common substrate of receptor tyrosine kinases under physiological conditions and that among the analyzed receptors (Ret, epidermal growth factor receptor, and TrkA) it is activated specifically by Ret. Overexpression of Rai in neuronal cell lines promoted survival by reducing apoptosis both under conditions of limited availability of the Ret ligand glial cell line-derived neurotrophic factor (GDNF) and in the absence of Ret activation. Overexpressed Rai resulted in the potentiation of the Ret-dependent activation of phosphatidylinositol 3-kinase (PI3K) and Akt. Notably, increased Akt phosphorylation and PI3K activity were also found under basal conditions, e.g., in serum-starved neuronal cells. Phosphorylated and hypophosphorylated Rai proteins form a constitutive complex with the p85 subunit of PI3K: upon Ret triggering, the Rai-PI3K complex is recruited to the tyrosine-phosphorylated Ret receptor through the binding of the Rai PTB domain to tyrosine 1062 of Ret. In neurons treated with low concentrations of GDNF, the prosurvival effect of Rai depends on Rai phosphorylation and Ret activation. In the absence of Ret activation, the prosurvival effect of Rai is, instead, phosphorylation independent. Finally, we showed that overexpression of Rai, at variance with Shc, had no effects on the early peak of mitogen-activated protein kinase (MAPK) activation, whereas it increased its activation at later time points. Phosphorylated Rai, however, was not found in complexes with Grb2. We propose that Rai potentiates the MAPK and PI3K signaling pathways and regulates Ret-dependent and -independent survival signals.

Present address: Istituto di Patologia Generale, Perugia University, 06100 Perugia, Italy.

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