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Insulin Receptor Substrate 4 Couples the Leptin Receptor to Multiple Signaling Pathways

Department of Medical Protein Research (J.W., A.-S.D.S., D.C., J.T.), VIB, and Department of Biochemistry (J.W., A.-S.D.S., D.C., J.T.), Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; and Department of Physiology (D.B.), University of Toronto, Ontario, Canada M5S 1A8

Address all correspondence and requests for reprints to: Jan Tavernier, University of Ghent, A. Baertsoenkaai 3, 9000 Ghent, Belgium. E-mail: jan.tavernier{at}UGent.be.

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 C, and the suppressor of cytokine signaling (SOCS) family members SOCS2, SOCS6, and SOCS7 and thus can modulate LR signaling.