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Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1.

ABSTRACT: 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.

SUBMITTER: Caetano FA

PROVIDER: S-EPMC2739057 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1.

Caetano Fabiana A FA Lopes Marilene H MH Hajj Glaucia N M GN Machado Cleiton F CF Pinto Arantes Camila C Magalhães Ana C AC Vieira Mônica De Paoli B Mde P Américo Tatiana A TA Massensini Andre R AR Priola Suzette A SA Vorberg Ina I Gomez Marcus V MV Linden Rafael R Prado Vania F VF Martins Vilma R VR Prado Marco A M MA

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080601 26

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 devo ...[more]

PMID: 18579743

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Project description:Mixed lineage kinase 3 (MLK3) functions in migration and/or invasion of several human cancers; however, the role of MLK3 in colorectal cancer (CRC) invasion is unknown. MLK3 is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) which activates MAPK pathways through either kinase-dependent or -independent mechanisms. Human colorectal tumors display increased levels of reactive oxygen species (ROS) or oxidative stress. ROS, such as H2O2, are important for carcinogenesis and activate MAPK signaling pathways. In human colorectal carcinoma (HCT116) cells treated with H2O2, extracellular signal-regulated kinases 1 and 2 (ERK1/2) were activated and MLK3 exhibited reduced electrophoretic mobility (shift) in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which was eliminated by phosphatase treatment. Pretreatment with the ROS scavenger N-acetyl-L-cysteine, the ERK1/2 inhibitor UO126, or ERK1/2 siRNA knockdown blocked the H2O2-induced shift of MLK3, while MLK3 inhibition with Cep1347 did not. In co-immunoprecipitation experiments performed on H2O2-treated HCT116 cells, endogenous MLK3 associated with endogenous ERK1/2 and B-Raf. Active ERK1 phosphorylated kinase dead FLAG-MLK3 in vitro, whereas ERK1 phosphorylation of kinase dead FLAG-MLK3-S705A-S758A was reduced. Both MLK3 siRNA knockdown and FLAG-MLK3-S705A-S758A expression decreased ERK1/2 activation in H2O2-treated cells. Prolonged H2O2 treatment activated ERK1/2 and promoted invasion of colon cancer cells, which was attenuated by MLK3 siRNA knockdown. Furthermore, S705A-S758A-FLAG-MLK3 demonstrated decreased oxidative-stress induced colon cancer cell invasion, but increased interaction with GST-B-Raf as compared with wild-type-FLAG-MLK3 in H2O2-treated cells. These results suggest oxidative stress stimulates an ERK1/2-dependent phosphorylation of MLK3 on Ser705 and Ser758, which promotes MLK3-dependent B-Raf and ERK1/2 activation; this positive feedback loop enhances the invasion of colon cancer cells.

Dataset Information

Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1.

Publications

Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1.

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