Rabiee, Atefeh, Krueger, Marcus, Ardenkjaer-Larsen, Jacob ORCID: 0000-0001-6974-6490, Kahn, C. Ronald and Emanuelli, Brice ORCID: 0000-0001-5795-5666 (2018). Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action. Cell. Signal., 47. S. 1 - 16. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1873-3913

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Abstract

Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type, IRS-1(-/-) and IRS-2(-/-) mice in the basal and IGF-1-stimulated states. We applied stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of changes in protein phosphorylation. We found similar to 10% of the 6262 unique phosphorylation sites detected to be regulated by IGF-1. These regulated sites included previously reported substrates of the insulin/IGF-1 signalling pathway, as well as novel substrates including Nuclear Factor I X and Semaphorin-4B. In silica prediction suggests the protein kinase B (PKB), protein kinase C (PKC), and cyclin-dependent kinase (CDK) as the main mediators of these phosphorylation events. Importantly, we found preferential phosphorylation patterns depending on the presence of either IRS-1 or IRS-2, which was associated with specific sets of kinases involved in signal transduction downstream of these substrates such as PDHK1, MAPK3, and PKD1 for IRS-1, and PIN1 and PKC beta for IRS-2. Overall, by generating a comprehensive phosphoproteomic profile from brown preadipocyte cells in response to IGF-1 stimulation, we reveal both common and distinct insulin/IGF-1 signalling events mediated by specific IRS proteins.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rabiee, AtefehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ardenkjaer-Larsen, JacobUNSPECIFIEDorcid.org/0000-0001-6974-6490UNSPECIFIED
Kahn, C. RonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Emanuelli, BriceUNSPECIFIEDorcid.org/0000-0001-5795-5666UNSPECIFIED
URN: urn:nbn:de:hbz:38-182367
DOI: 10.1016/j.cellsig.2018.03.003
Journal or Publication Title: Cell. Signal.
Volume: 47
Page Range: S. 1 - 16
Date: 2018
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1873-3913
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ADIPOCYTE DIFFERENTIATION; GROWTH-FACTOR; CROSS-TALK; PROTEIN; PHOSPHORYLATION; REVEALS; GLUCOSE; MICE; PHOSPHOPROTEOME; UBIQUITINATIONMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18236

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