Insulin receptor substrate 1 is a substrate of the Pim protein kinases

Persistent Link:
http://hdl.handle.net/10150/614947
Title:
Insulin receptor substrate 1 is a substrate of the Pim protein kinases
Author:
Song, Jin H.; Padi, Sathish K. R.; Luevano, Libia A.; Minden, Mark D.; DeAngelo, Daniel J.; Hardiman, Gary; Ball, Lauren E.; Warfel, Noel A.; Kraft, Andrew S.
Affiliation:
Univ Arizona, Dept Cellular & Mol Med; Univ Arizona, Ctr Canc
Issue Date:
2016-03-04
Publisher:
IMPACT JOURNALS LLC
Journal:
ONCOTARGET
Rights:
Creative Commons Attribution License
Collection Information:
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
Abstract:
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.
DOI:
10.18632/oncotarget.7918
Keywords:
insulin; IGF1; IRS1; Pim kinase; Pim kinase inhibitor
Version:
Final published version
Sponsors:
This project was supported by University of Arizona Cancer Center Support Grant P30CA023074, and NIH R01CA173200, DOD W81XWH-12-1-0560 to ASK.

Full metadata record

DC FieldValue Language
dc.contributor.authorSong, Jin H.en
dc.contributor.authorPadi, Sathish K. R.en
dc.contributor.authorLuevano, Libia A.en
dc.contributor.authorMinden, Mark D.en
dc.contributor.authorDeAngelo, Daniel J.en
dc.contributor.authorHardiman, Garyen
dc.contributor.authorBall, Lauren E.en
dc.contributor.authorWarfel, Noel A.en
dc.contributor.authorKraft, Andrew S.en
dc.date.accessioned2016-06-29T00:21:46Z-
dc.date.available2016-06-29T00:21:46Z-
dc.date.issued2016-03-04-
dc.identifier.doi10.18632/oncotarget.7918-
dc.identifier.urihttp://hdl.handle.net/10150/614947-
dc.description.abstractThe 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.en
dc.description.sponsorshipThis project was supported by University of Arizona Cancer Center Support Grant P30CA023074, and NIH R01CA173200, DOD W81XWH-12-1-0560 to ASK.en
dc.language.isoenen
dc.publisherIMPACT JOURNALS LLCen
dc.rightsCreative Commons Attribution Licenseen
dc.subjectinsulinen
dc.subjectIGF1en
dc.subjectIRS1en
dc.subjectPim kinaseen
dc.subjectPim kinase inhibitoren
dc.titleInsulin receptor substrate 1 is a substrate of the Pim protein kinasesen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Cellular & Mol Meden
dc.contributor.departmentUniv Arizona, Ctr Cancen
dc.identifier.journalONCOTARGETen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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