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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 andMarco 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 (PrPC) at the cell surface, resulting in neuroprotection and increased neuritogenesis. Here, we investigated whether STI1 triggers PrPC trafficking and tested whether this process controls PrPC-dependent signaling. We found that STI1, but not a STI1 mutant unable to bind PrPC, induced PrPC endocytosis. STI1-induced signaling did not occur in cells devoid of endogenous PrPC; however, heterologous expression of PrPC reconstituted both PKA and ERK1/2 activation. In contrast, a PrPC 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 PrPC 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
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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