The extracellular regulated kinase-1 (ERK1) controls regulated α-secretase-mediated processing, promoter transactivation, and mRNA levels of the cellular prion protein

Abstract

The α-secretases A disintegrin and metalloprotease 10 (ADAM10) and ADAM17 trigger constitutive and regulated processing of the cellular prion protein (PrPc) yielding N1 fragment. The latter depends on protein kinase C (PKC)-coupled M1/M3 muscarinic receptor activation and subsequent phosphorylation of ADAM17 on its intracytoplasmic threonine 735. Here we show that regulated PrPc processing and ADAM17 phosphorylation and activation are controlled by the extracellular-regulated kinase-1/MAP-ERK kinase (ERK1/MEK) cascade. Thus, reductions of ERK1 or MEK activities by dominantnegative analogs, pharmacological inhibition, or genetic ablation all impair N1 secretion, whereas constitutively active proteins increase N1 recovery in the conditioned medium. Interestingly, we also observed an ERK1-mediated enhanced expression of PrPc. We demonstrate that the ERK1-associated increase in PrPc promoter transactivation and mRNA levels involve transcription factor AP-1 as a downstream effector. Altogether, our data identify ERK1 as an important regulator of PrPc cellular homeostasis and indicate that this kinase exerts a dual control of PrPc levels through transcriptional and posttranscriptional mechanisms. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.