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The Journal of Neuroscience, December 7, 2005, 25(49):11330-11339; doi:10.1523/JNEUROSCI.2313-05.2005

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Neurobiology of Disease
Interaction of Cellular Prion and Stress-Inducible Protein 1 Promotes Neuritogenesis and Neuroprotection by Distinct Signaling Pathways

Marilene H. Lopes,^1,2 * Glaucia N. M. Hajj,^1 * Angelita G. Muras,^1,2 Gabriel L. Mancini,¹ Rosa M. P. S. Castro,^1,2 Karina C. B. Ribeiro,² Ricardo R. Brentani,^1,2 Rafael Linden,³ and Vilma R. Martins^1,2

¹Ludwig Institute for Cancer Research, São Paulo Branch, and ²Centro de Tratamento e Pesquisa–Hospital do Câncer, 01509-010 São Paulo, Brazil, and ³Instituto de Biofísica da Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco G, Cidade Universitária, 21949-900 Rio de Janeiro, Brazil

Understanding the physiological function of the cellular prion (PrP^c) depends on the investigation of PrP^c-interacting proteins. Stress-inducible protein 1 (STI1) is a specific PrP^c ligand that promotes neuroprotection of retinal neurons through cAMP-dependent protein kinase A (PKA). Here, we examined the signaling pathways and functional consequences of the PrP^c interaction with STI1 in hippocampal neurons. Both PrP^c and STI1 are abundantly expressed and highly colocalized in the hippocampus in situ, indicating that they can interact in vivo. Recombinant STI1 (His₆-STI1) added to hippocampal cultures interacts with PrP^c at the neuronal surface and elicits neuritogenesis in wild-type neurons but not in PrP^c-null cells. This effect was abolished by antibodies against either PrP^c or STI1 and was dependent on the STI1 domain that binds PrP^c. Binding of these proteins induced the phosphorylation/activation of the mitogen-activated protein kinase, which was essential for STI1-promoted neuritogenesis. His₆-STI1, but not its counterpart lacking the PrP^c binding site, prevented cell death via PKA activation. These results demonstrate that two parallel effects of the PrP^c–STI1 interaction, neuritogenesis and neuroprotection, are mediated by distinct signaling pathways.

Key words: cellular prion protein; MAPK; neuritogenesis; neuroprotection; PKA; STI1

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Received Feb 2, 2005; revised October 19, 2005; accepted October 22, 2005.

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