Insulin receptor substrate 4 couples the leptin receptor to multiple signaling pathways.
Leptin is an adipokine that regulates food intake and energy expenditure by activating its hypothalamic leptin receptor (LR). Members of the insulin receptor substrate (IRS) family serve as adaptor proteins in the signaling pathways of several cytokines and hormones and a role for IRS2 in central leptin physiology is well established. Using mammalian protein-protein interaction trap (MAPPIT), a cytokine receptor-based two-hybrid method, in the N38 hypothalamic cell line, we here demonstrate that also IRS4 interacts with the LR. This recruitment is leptin dependent and requires phosphorylation of the Y1077 motif of the LR. Domain mapping of IRS4 revealed the critical role of the pleckstrin homology domain for full interaction. In line with its function as an adaptor protein, IRS4 interacted with the regulatory p85 subunit of the phosphatidylinositol 3-kinase, phospholipase Cgamma, and the suppressor of cytokine signaling (SOCS) family members SOCS2, SOCS6, and SOCS7 and thus can modulate LR signaling.
Wauman
Joris
J
Department of Medical Protein Research, University of Ghent, A. Baertsoenkaai 3, 9000 Ghent, Belgium.
De Smet
Anne-Sophie
AS
Catteeuw
Dominiek
D
Belsham
Denise
D
Tavernier
Jan
J
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D006801:Humans; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D054411:Receptors, Leptin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C107686:IRS4 protein, human; D055504:Insulin Receptor Substrate Proteins; C491531:Irs4 protein, mouse; D020738:Leptin; D054411:Receptors, Leptin