Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways.
Understanding the physiological function of the cellular prion (PrPc) depends on the investigation of PrPc-interacting proteins. Stress-inducible protein 1 (STI1) is a specific PrPc 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 PrPc interaction with STI1 in hippocampal neurons. Both PrPc 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 PrPc at the neuronal surface and elicits neuritogenesis in wild-type neurons but not in PrPc-null cells. This effect was abolished by antibodies against either PrPc or STI1 and was dependent on the STI1 domain that binds PrPc. 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 PrPc binding site, prevented cell death via PKA activation. These results demonstrate that two parallel effects of the PrPc-STI1 interaction, neuritogenesis and neuroprotection, are mediated by distinct signaling pathways.
Lopes
Marilene H
MH
Ludwig Institute for Cancer Research, São Paulo Branch, 01509-010 São Paulo, Brazil.
Hajj
Glaucia N M
GN
Muras
Angelita G
AG
Mancini
Gabriel L
GL
Castro
Rosa M P S
RM
Ribeiro
Karina C B
KC
Brentani
Ricardo R
RR
Linden
Rafael
R
Martins
Vilma R
VR
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016501:Neurites / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D006360:Heat-Shock Proteins; D011328:Prions; C489791:Stip1 protein, mouse