Insulin receptor substrate 1 is a substrate of the Pim protein kinases
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Jin H. Song1,2, Sathish K. R. Padi2, Libia A. Luevano2, Mark D. Minden3, Daniel J. DeAngelo4, Gary Hardiman5, Lauren E. Ball6, Noel A. Warfel1,2, Andrew S. Kraft2
1Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
2University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada
4Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
5Departments of Medicine and Public Health Sciences and The Center for Genomics Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
6Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC 29425, USA
Jin H. Song, e-mail: [email protected]
Andrew S. Kraft, e-mail: [email protected]
Keywords: insulin, IGF1, IRS1, Pim kinase, Pim kinase inhibitor
Received: December 28, 2015 Accepted: February 14, 2016 Published: March 04, 2016
The Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy.
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