title: Profiling of p5, a 24 Amino Acid Inhibitory Peptide Derived from the CDK5 Activator, p35 CDKR1 Against 70 Protein Kinases.
abstract: Cyclin-dependent kinase 5 (CDK5) is a multifunctional serine/threonine kinase that regulates a large number of neuronal processes essential for nervous system development and function with its activator p35 CDK5R1. Upon neuronal insults, p35 is proteolyzed and cleaved to p25 producing deregulation and hyperactivation of CDK5 (CDK5/p25), implicated in tau hyperphosphorylation, a pathology in some neurodegenerative diseases. A truncated, 24 amino acid peptide, p5, derived from p35 inhibits the deregulated CDK5 phosphotransferase activity and ameliorates Alzheimer's disease (AD) phenotypes in AD model mice. In the present study, we have screened a diverse panel of 70 human protein kinases for their sensitivities to p5, and a subset of these to p35. At least 16 of the tested protein kinases exhibited IC50 values that were 250 μM or less, with CAMK4, ZAP70, SGK1, and PIM1 showing greater sensitivity to inhibition by p5 than CDK5/p35 and CDK5/p25. In contrast, the p5 peptide modestly activated LKB1 and GSK3β. A sub set of kinases screened against p35 showed that activity of CAMK4 in the absence of calcium and calmodulin was also markedly inhibited by p35. The Cyclin Y-dependent kinases PFTK1 (CDK14) and PCTK1 (CDK16) were activated by p35 at least 10-fold in the absence of Cyclin Y and by approximately 50% in its presence. These findings provide additional insights into the mechanisms of action for p5 and p35 in the regulation of protein phosphorylation in the nervous system.
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: B K
authors: BK
authors: Binukumar
authors: Kinexus Bioinformatics Corporation; Division of Neurology, Department of Medicine, University of British Columbia, BC, Canada.
authors: Steven L
authors: SL
authors: Pelech
authors: Kinexus Bioinformatics Corporation; Division of Neurology, Department of Medicine, University of British Columbia, BC, Canada.
authors: Catherine
authors: C
authors: Sutter
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: Varsha
authors: V
authors: Shukla
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: Niranjana D
authors: ND
authors: Amin
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: Philip
authors: P
authors: Grant
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: Manju
authors: M
authors: Bhaskar
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: Suzanne
authors: S
authors: Skuntz
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: Joseph
authors: J
authors: Steiner
authors: National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.
authors: Harish C
authors: HC
authors: Pant
mesh_terms: D000595:Amino Acid Sequence; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C089495:neuronal Cdk5 activator (p25-p35); C553404:p5 protein, human; D011494:Protein Kinases; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human
keywords: Alzheimer’s disease; cyclin-dependent kinase 5 activator; p35 CDK5R1; tau 
  phosphorylation