PT  - JOURNAL ARTICLE
AU  - Fabiana A. Caetano
AU  - Marilene H. Lopes
AU  - Glaucia N. M. Hajj
AU  - Cleiton F. Machado
AU  - Camila Pinto Arantes
AU  - Ana C. Magalhães
AU  - Mônica De Paoli B. Vieira
AU  - Tatiana A. Américo
AU  - Andre R. Massensini
AU  - Suzette A. Priola
AU  - Ina Vorberg
AU  - Marcus V. Gomez
AU  - Rafael Linden
AU  - Vania F. Prado
AU  - Vilma R. Martins
AU  - Marco A. M. Prado
TI  - Endocytosis of Prion Protein Is Required for ERK1/2 Signaling Induced by Stress-Inducible Protein 1
AID  - 10.1523/JNEUROSCI.1701-08.2008
DP  - 2008 Jun 25
TA  - The Journal of Neuroscience
PG  - 6691--6702
VI  - 28
IP  - 26
4099  - http://www.jneurosci.org/content/28/26/6691.short
4100  - http://www.jneurosci.org/content/28/26/6691.full
SO  - J. Neurosci.2008 Jun 25; 28
AB  - 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.