Interaction between serine phosphorylated IRS-1 and β1-integrin affects the stability of neuronal processes

Authors

  • Jin Ying Wang,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Elisa Gualco,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Francesca Peruzzi,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Bassel E. Sawaya,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Giovanni Passiatore,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Cezary Marcinkiewicz,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Izabella Staniszewska,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Pasquale Ferrante,

    1. Laboratory of Molecular Medicine and Biotechnologies, Don C. Gnocchi Foundation, Milan, Italy
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  • Shohreh Amini,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
    2. Department of Biology, Temple University, Philadelphia, Pennsylvania
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  • Kamel Khalili,

    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
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  • Krzysztof Reiss

    Corresponding author
    1. Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania
    • Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, 1900 North 12th Street, Biology Life Science Building, Philadelphia, PA 19122
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Abstract

Tumor necrosis factor-α (TNFα) released in the brain by HIV-activated macrophages/microglia is suspected to compromise neuronal survival. Previously, we have demonstrated that activated receptor for insulin-like growth factor I (IGF-IR) protects neurons from TNFα-induced neuronal damage (Wang et al. [ 2006] J. Neurosci. Res. 83:7–18). Because TNFα triggers phosphorylation of insulin receptor substrate 1 (IRS-1) on serine residues (pS-IRS-1; Rui et al. [ 2001] J. Clin. Invest. 107:181–189), and pS-IRS-1 binds integrins (Reiss et al. [ 2001] Oncogene 20:490–500), we asked how these events affect neuronal processes. We show that β1-integrin and pS-IRS-1 colocalize in PC12 cells and in primary cortical neurons. TNFα treatment elevated membrane-associated pS-IRS-1, enhanced pS-IRS-1 interaction with β1-integrin, and attenuated cell attachment to collagen IV. In contrast, IGF-I inhibited pS-IRS-1–β1-integrin complexes and improved cell attachment. The domain of IRS-1 involved in β1-integrin binding mapped between amino acids 426 and 740, and the expression of 426–740/IRS-1 mutant attenuated neuronal outgrowth. Our results indicate that TNFα facilitates the interaction of pS-IRS-1 and β1-integrin and destabilizes neuronal processes. IGF-I counteracts TNFα-mediated accumulation of pS-IRS-1–β1-integrin complexes supporting the stability of neuronal processes. © 2007 Wiley-Liss, Inc.

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