Interaction between serine phosphorylated IRS-1 and beta1-integrin affects the stability of neuronal processes.
Tumor necrosis factor-alpha (TNFalpha) 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 TNFalpha-induced neuronal damage (Wang et al. [ 2006] J. Neurosci. Res. 83:7-18). Because TNFalpha 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 beta1-integrin and pS-IRS-1 colocalize in PC12 cells and in primary cortical neurons. TNFalpha treatment elevated membrane-associated pS-IRS-1, enhanced pS-IRS-1 interaction with beta1-integrin, and attenuated cell attachment to collagen IV. In contrast, IGF-I inhibited pS-IRS-1-beta1-integrin complexes and improved cell attachment. The domain of IRS-1 involved in beta1-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 TNFalpha facilitates the interaction of pS-IRS-1 and beta1-integrin and destabilizes neuronal processes. IGF-I counteracts TNFalpha-mediated accumulation of pS-IRS-1-beta1-integrin complexes supporting the stability of neuronal processes.
Wang
Jin Ying
JY
Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania 19122, USA.
Gualco
Elisa
E
Peruzzi
Francesca
F
Sawaya
Bassel E
BE
Passiatore
Giovanni
G
Marcinkiewicz
Cezary
C
Staniszewska
Izabella
I
Ferrante
Pasquale
P
Amini
Shohreh
S
Khalili
Kamel
K
Reiss
Krzysztof
K
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D012694:Serine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D055504:Insulin Receptor Substrate Proteins; D019012:Integrin beta1; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D007334:Insulin-Like Growth Factor I