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Journal of Biochemistry Advance Access published online on January 18, 2007
Journal of Biochemistry, doi:10.1093/jb/mvm040
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© 2007 The Japanese Biochemical Society

Pim Kinase Substrate Identification and Specificity

Charline Peng1, Axel Knebel2, Nick A. Morrice3, Xiang J Li1, Kevin Barringer1, Jun Li1, Scott Jakes1, Brian Werneburg1 and Lian Wang1,*

1 Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, Ridgefield, CT 06877, USA
2 Kinasource Ltd, Unit 9 South Dudhope Complex, 77 Douglas Street, Dundee, DD1 5AN, Scotland, UK
3 MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dow Street, DD1 5EH, Scotland, UK

*Corresponding author: Dept of Cardiovascular Disease, Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, Ridgefield, CT 06877. email address: lwang{at}rdg.boehringer-ingelheim.com

Received August 14, 2006; Accepted December 30, 2006


  Abstract

The Pim family of Ser/Thr kinases has been implicated in the process of lymphomagenesis and cell survival. Known substrates of Pim kinases are few and poorly characterized. In this study we set out to identify novel Pim-2 substrates using the KESTREL (Kinase Substrate Tracking and Elucidation) approach. Two potential substrates, eukaryotic initiation factor 4B (eIF4B) and apoptosis inhibitor 5 (API-5), were identified from rat thymus extracts. Sequence comparison of the Pim-2 kinase phosphorylation sites of eIF4B and mouse BAD, the only other known Pim-2 substrate, revealed conserved amino acids preceding the phosphorylated serine residue. Stepwise replacement of the conserved residues produced a consensus sequence for Pim kinases recognition: RXRHXS. Pim-1 and Pim-2 catalyzed the phosphorylation of this recognition sequence 20-fold more efficiently than the original (K/R-K/R-R-K/R-L-S/T-a; a = small chain amino acid) Pim-1 phosphorylation site. The identification of the novel Pim kinases consensus sequence provides a more sensitive and versatile peptide based assay for screening modulators of Pim kinases activity.

Key Words: Pim-2, Pim-1, eIF4B, peptide substrate, consensus sequence, KESTREL, kinase assay


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