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ACS Chem Neurosci. 2018 Dec 19;9(12):3072-3085. doi: 10.1021/acschemneuro.8b00284. Epub 2018 Aug 13.

Structural Analysis of Hippocampal Kinase Signal Transduction.

Author information

1
Department of Molecular Medicine , The Scripps Research Institute , La Jolla , California 92037 , United States.
2
Department of Neuroscience , The Scripps Research Institute , La Jolla , California 92037 , United States.
3
Department of Biochemistry, Microbiology and Immunology and Ottawa Institute of Systems Biology , University of Ottawa , Ottawa , ON K1H 8M5 , Canada.
4
Department of Psychiatry , UCSD , La Jolla , California 92093 , United States.

Abstract

Kinases are a major clinical target for human diseases. Identifying the proteins that interact with kinases in vivo will provide information on unreported substrates and will potentially lead to more specific methods for therapeutic kinase regulation. Here, endogenous immunoprecipitations of evolutionally distinct kinases (i.e., Akt, ERK2, and CAMK2) from rodent hippocampi were analyzed by mass spectrometry to generate three highly confident kinase protein-protein interaction networks. Proteins of similar function were identified in the networks, suggesting a universal model for kinase signaling complexes. Protein interactions were observed between kinases with reported symbiotic relationships. The kinase networks were significantly enriched in genes associated with specific neurodevelopmental disorders providing novel structural connections between these disease-associated genes. To demonstrate a functional relationship between the kinases and the network, pharmacological manipulation of Akt in hippocampal slices was shown to regulate the activity of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel(HCN1), which was identified in the Akt network. Overall, the kinase protein-protein interaction networks provide molecular insight of the spatial complexity of in vivo kinase signal transduction which is required to achieve the therapeutic potential of kinase manipulation in the brain.

KEYWORDS:

Akt; HCN1; Kinase; hippocampus; mass spectrometry; protein−protein interactions

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