Next Article in Journal
Genome-Wide Identification of PIFs in Grapes (Vitis vinifera L.) and Their Transcriptional Analysis under Lighting/Shading Conditions
Next Article in Special Issue
Lysine Acetylation Regulates Alanyl-tRNA Synthetase Activity in Escherichia coli
Previous Article in Journal
A Computational Method for Classifying Different Human Tissues with Quantitatively Tissue-Specific Expressed Genes
Previous Article in Special Issue
Genome-Wide Quantification of the Effect of Gene Overexpression on Escherichia coli Growth
Article Menu
Issue 9 (September) cover image

Export Article

Open AccessFeature PaperArticle
Genes 2018, 9(9), 450;

Phosphorylation-Dependent Inhibition of Akt1

Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada
Department of Chemistry, Faculty of Science, The University of Western Ontario, London, ON N6A 5C1, Canada
Author to whom correspondence should be addressed.
Received: 20 July 2018 / Revised: 10 August 2018 / Accepted: 10 August 2018 / Published: 7 September 2018
(This article belongs to the Special Issue Synthetic DNA and RNA Programming)
Full-Text   |   PDF [3207 KB, uploaded 7 September 2018]   |  


Protein kinase B (Akt1) is a proto-oncogene that is overactive in most cancers. Akt1 activation requires phosphorylation at Thr308; phosphorylation at Ser473 further enhances catalytic activity. Akt1 activity is also regulated via interactions between the kinase domain and the N-terminal auto-inhibitory pleckstrin homology (PH) domain. As it was previously difficult to produce Akt1 in site-specific phosphorylated forms, the contribution of each activating phosphorylation site to auto-inhibition was unknown. Using a combination of genetic code expansion and in vivo enzymatic phosphorylation, we produced Akt1 variants containing programmed phosphorylation to probe the interplay between Akt1 phosphorylation status and the auto-inhibitory function of the PH domain. Deletion of the PH domain increased the enzyme activity for all three phosphorylated Akt1 variants. For the doubly phosphorylated enzyme, deletion of the PH domain relieved auto-inhibition by 295-fold. We next found that phosphorylation at Ser473 provided resistance to chemical inhibition by Akti-1/2 inhibitor VIII. The Akti-1/2 inhibitor was most effective against pAkt1T308 and showed four-fold decreased potency with Akt1 variants phosphorylated at Ser473. The data highlight the need to design more potent Akt1 inhibitors that are effective against the doubly phosphorylated and most pathogenic form of Akt1. View Full-Text
Keywords: genetic code expansion; protein kinase B; phosphoinositide dependent kinase 1; phosphoseryl-tRNA synthetase; tRNASep genetic code expansion; protein kinase B; phosphoinositide dependent kinase 1; phosphoseryl-tRNA synthetase; tRNASep

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

Balasuriya, N.; McKenna, M.; Liu, X.; Li, S.S.C.; O’Donoghue, P. Phosphorylation-Dependent Inhibition of Akt1. Genes 2018, 9, 450.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Genes EISSN 2073-4425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top