PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons.
Kent Z Q WangErin SteerP Anthony OteroNicholas W BatemanMary Hongying ChengAna Ligia ScottChristine WuIvet BaharYu-Tzu ShihYi-Ping HsuehCharleen T ChuPublished in: eNeuro (2018)
While PTEN-induced kinase 1 (PINK1) is well characterized for its role in mitochondrial homeostasis, much less is known concerning its ability to prevent synaptodendritic degeneration. Using unbiased proteomic methods, we identified valosin-containing protein (VCP) as a major PINK1-interacting protein. RNAi studies demonstrate that both VCP and its cofactor NSFL1C/p47 are necessary for the ability of PINK1 to increase dendritic complexity. Moreover, PINK1 regulates phosphorylation of p47, but not the VCP co-factor UFD1. Although neither VCP nor p47 interact directly with PKA, we found that PINK1 binds and phosphorylates the catalytic subunit of PKA at T197 [PKAcat(pT197)], a site known to activate the PKA holoenzyme. PKA in turn phosphorylates p47 at a novel site (S176) to regulate dendritic complexity. Given that PINK1 physically interacts with both the PKA holoenzyme and the VCP-p47 complex to promote dendritic arborization, we propose that PINK1 scaffolds a novel PINK1-VCP-PKA-p47 signaling pathway to orchestrate dendritogenesis in neurons. These findings highlight an important mechanism by which proteins genetically implicated in Parkinson's disease (PD; PINK1) and frontotemporal dementia (FTD; VCP) interact to support the health and maintenance of neuronal arbors.
Keyphrases
- signaling pathway
- protein kinase
- healthcare
- public health
- mental health
- binding protein
- oxidative stress
- epithelial mesenchymal transition
- risk assessment
- pi k akt
- brain injury
- protein protein
- spinal cord injury
- induced apoptosis
- endothelial cells
- health information
- tyrosine kinase
- endoplasmic reticulum stress
- case control
- single molecule