Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: Cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance

Jeong A. Kim, Deborah C. Yeh, Marel Ver, Yunhua Li, Andrea Carranza, Thomas P. Conrads, Timothy D. Veenstra, Maureen Harrington, Michael J. Quon

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Abstract

Inflammation contributes to insulin resistance in diabetes and obesity. Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-α-treated cells. In NIH-3T3IR cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. This association was increased by treatment of cells with TNF-α. Using mass spectrometry, we identified Ser24 in the pleckstrin homology (PH) domain of IRS-I as a specific phosphorylation site for mPLK, IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser24) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. Importantly, endogenous mPLK/IRAK was activated in response to TNF-α or interleukin 1 treatment of primary adipose cells. In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser24, we found that interleukin-1 or TNF-α treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser24. We conclude that IRS-1 is a novel physiological substrate for mPLK. TNF-α-regulated phosphorylation at Ser24 in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance.

Original languageEnglish
Pages (from-to)23173-23183
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number24
DOIs
StatePublished - Jun 17 2005

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Interleukin-1 Receptor-Associated Kinases
Insulin Receptor Substrate Proteins
Phosphorylation
Insulin Resistance
Phosphotransferases
Insulin
Tumor Necrosis Factor-alpha
Interleukin-1
Cells
Phospho-Specific Antibodies
Inflammation
Insulin Receptor
Substrates
Medical problems
Phosphatidylinositol 3-Kinases
Mass spectrometry
Tyrosine
Pleckstrin Homology Domains
platelet protein P47
Rats

ASJC Scopus subject areas

  • Biochemistry

Cite this

Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse Pelle-like kinase/interleukin-1 receptor-associated kinase : Cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. / Kim, Jeong A.; Yeh, Deborah C.; Ver, Marel; Li, Yunhua; Carranza, Andrea; Conrads, Thomas P.; Veenstra, Timothy D.; Harrington, Maureen; Quon, Michael J.

In: Journal of Biological Chemistry, Vol. 280, No. 24, 17.06.2005, p. 23173-23183.

Research output: Contribution to journalArticle

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abstract = "Inflammation contributes to insulin resistance in diabetes and obesity. Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-α-treated cells. In NIH-3T3IR cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. This association was increased by treatment of cells with TNF-α. Using mass spectrometry, we identified Ser24 in the pleckstrin homology (PH) domain of IRS-I as a specific phosphorylation site for mPLK, IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser24) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. Importantly, endogenous mPLK/IRAK was activated in response to TNF-α or interleukin 1 treatment of primary adipose cells. In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser24, we found that interleukin-1 or TNF-α treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser24. We conclude that IRS-1 is a novel physiological substrate for mPLK. TNF-α-regulated phosphorylation at Ser24 in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance.",
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AU - Yeh, Deborah C.

AU - Ver, Marel

AU - Li, Yunhua

AU - Carranza, Andrea

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AU - Harrington, Maureen

AU - Quon, Michael J.

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