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 (PrP c ) depends on the investigation of PrP c -interacting proteins. Stress-inducible protein 1 (STI1) is a specific PrP c 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 PrP c interaction with STI1 in hippocampal neurons. Both PrP c and STI1 are abundantly expressed and highly colocalized in the hippocampus in situ , indicating that they can interact in vivo . Recombinant STI1 (His 6 -STI1) added to hippocampal cultures interacts with PrP c at the neuronal surface and elicits neuritogenesis in wild-type neurons but not in PrP c -null cells. This effect was abolished by antibodies against either PrP c or STI1 and was dependent on the STI1 domain that binds PrP c . Binding of these proteins induced the phosphorylation/activation of the mitogen-activated protein kinase, which was essential for STI1-promoted neuritogenesis. His 6 -STI1, but not its counterpart lacking the PrP c binding site, prevented cell death via PKA activation. These results demonstrate that two parallel effects of the PrP c –STI1 interaction, neuritogenesis and neuroprotection, are mediated by distinct signaling pathways.