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Submitted on August 28, 2001
Accepted on April 22, 2003
1 The Sackler Institute for Muscular Skeletal Research, Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, UK and Cardiology Branch, NHLBI, NIH, Bethesda, MD 20892-1755, USA, Department of Oncology and Neurosciences, Section of Medical Oncology, Universita' "G. D'Annunzio", Via dei Vestini 1, 66100 Chieti, ITALY and Chair of Endocrinology, 2Faculty of Medicine, Universita' "La Sapienza" di Roma, Centro Ricerca Ospedale S. Pietro Fatebenefratelli, Via Cassia 600, 00189 Roma, ITALY., Present address: Department of Biomedical Sciences, Università degli Studi di Modena e Reggio Emilia, Via Campi 287, 41100 Modena, ITALY, These authors contributed equally to this work
* To whom correspondence should be addressed. 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 then 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 co-operative mechanisms both involving the PH domain.
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