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Role of Pleckstrin Homology Domain in Regulating Membrane Targeting and Metabolic Function of Insulin Receptor Substrate 3

The Sackler Institute for Muscular Skeletal Research (T.M., G.R., A.I., M.F.), Department of Medicine, University College London, London WC1E 6JJ, United Kingdom; Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20893-1632; Department of Oncology and Neurosciences (S.I.), Section of Medical Oncology, Universita’ "G. D’Annunzio," 66100 Chieti, Italy; and Chair of Endocrinology (S.S.), 2nd Faculty of Medicine, Universita’ "La Sapienza" di Roma, Centro Ricerca Ospedale S. Pietro Fatebenefratelli, Associazione Fatebenefratelli per la Ricerca, 00189 Rome, Italy

Address all correspondence and requests for reprints to: Marco Falasca, The Sackler Institute, University College London, Rayne Building, 5 University Street, London WC1E 6JJ, United Kingdom. E-mail: m.falasca{at}ucl.ac.uk.

The insulin receptor phosphorylates insulin receptor substrate (IRS) proteins on multiple tyrosine residues that act as docking sites to recruit a number of downstream signaling molecules. Here we show that IRS3 is localized both at the plasma membrane and in the nucleus. Interestingly, the nuclear localization of the protein is restricted to specific regions involved in mRNA processing and known as speckles. By using different truncated versions of the protein, we demonstrate that the pleckstrin homology (PH) domain is involved in IRS3 localization at the level of both plasma membrane and nucleus. To our knowledge this is the first report of a PH domain responsible for a nuclear targeting of the host protein. By site-directed mutagenesis, we identify residues within the PH domain critical for proper localization of IRS3. Mutations within the PH domain preventing IRS3 intracellular localization result in an inhibition of IRS3-induced glucose uptake. We conclude that the PH domain is required for IRS3 intracellular localization and, furthermore, that it has a key role in metabolic functions of IRS3. In particular, our data suggest that IRS3 intracellular localization at the plasma membrane and in the nucleus is the result of two different cooperative mechanisms both involving the PH domain.

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