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The Journal of Neuroscience, June 25, 2008, 28(26):6691-6702; doi:10.1523/JNEUROSCI.1701-08.2008

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Neurobiology of Disease
Endocytosis of Prion Protein Is Required for ERK1/2 Signaling Induced by Stress-Inducible Protein 1

Fabiana A. Caetano,^1 * Marilene H. Lopes,^4 * Glaucia N. M. Hajj,^4 * Cleiton F. Machado,⁴ Camila Pinto Arantes,^4,5 Ana C. Magalhães,¹ Mônica De Paoli B. Vieira,¹ Tatiana A. Américo,⁶ Andre R. Massensini,² Suzette A. Priola,⁷ Ina Vorberg,⁸ Marcus V. Gomez,¹ Rafael Linden,⁶ Vania F. Prado,³ Vilma R. Martins,⁴ and Marco A. M. Prado¹

¹Programa de Farmacologia Bioquímica e Molecular, Departamento de Farmacologia, ²Departamento de Fisiologia e Biofísica and ³Departamento de Bioquímica-Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG 30270-910, Belo Horizonte, Brazil, ⁴Ludwig Institute for Cancer Research–Hospital Alemão Oswaldo Cruz, SP 01323-903, São Paulo, Brazil, ⁵Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900, São Paulo, Brazil, ⁶Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21949-900, Rio de Janeiro, Brazil, ⁷Laboratory of Persistent Viral Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases Rocky Mountain Laboratories, Hamilton, Montana 59840, and ⁸Institute of Virology, Technical University of Munich, 81675 Munich, Germany

Correspondence should be addressed to either of the following: Vilma R. Martins, Ludwig Institute for Cancer Research, Rua Joao Julião 245 1A, SP 01323-903, São Paulo, Brazil, Email: vmartins{at}ludwig.org.br; or Marco A. M. Prado, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, MG 30270-910, Belo Horizonte, Brazil, E-mail: Email: mprado{at}icb.ufmg.br

The secreted cochaperone STI1 triggers activation of protein kinase A (PKA) and ERK1/2 signaling by interacting with the cellular prion (PrP^C) at the cell surface, resulting in neuroprotection and increased neuritogenesis. Here, we investigated whether STI1 triggers PrP^C trafficking and tested whether this process controls PrP^C-dependent signaling. We found that STI1, but not a STI1 mutant unable to bind PrP^C, induced PrP^C endocytosis. STI1-induced signaling did not occur in cells devoid of endogenous PrP^C; however, heterologous expression of PrP^C reconstituted both PKA and ERK1/2 activation. In contrast, a PrP^C mutant lacking endocytic activity was unable to promote ERK1/2 activation induced by STI1, whereas it reconstituted PKA activity in the same condition, suggesting a key role of endocytosis in the former process. The activation of ERK1/2 by STI1 was transient and appeared to depend on the interaction of the two proteins at the cell surface or shortly after internalization. Moreover, inhibition of dynamin activity by expression of a dominant-negative mutant caused the accumulation and colocalization of these proteins at the plasma membrane, suggesting that both proteins use a dynamin-dependent internalization pathway. These results show that PrP^C endocytosis is a necessary step to modulate STI1-dependent ERK1/2 signaling involved in neuritogenesis.

Key words: neurodegeneration; endocytosis; clathrin; raft; prion diseases; flotillin; ERK

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Received Oct. 22, 2007; accepted May 7, 2008.

Correspondence should be addressed to either of the following: Vilma R. Martins, Ludwig Institute for Cancer Research, Rua Joao Julião 245 1A, SP 01323-903, São Paulo, Brazil, Email: vmartins{at}ludwig.org.br; or Marco A. M. Prado, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, MG 30270-910, Belo Horizonte, Brazil, E-mail: Email: mprado{at}icb.ufmg.br

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