title: Involvement of IRS-1 interaction with ADAM10 in the regulation of neurite extension.
abstract: The insulin-like growth factor-1 (IGF-1) signaling pathway plays an important role in neuronal cell differentiation. Recent studies have shown that IGF-1 has the capacity to counteract the retraction of neuronal processes in response to inflammatory cytokines such as TNF-α, which is a known factor for neuronal injury in the central nervous system. This event is thought to be mediated via interference of TNF-α-induced interaction of β1-integrin with insulin receptor substrate-1 (IRS-1). Here, we demonstrate the interaction of IRS-1 with disintegrin and metalloproteinase ADAM10 through the N-terminal domain of IRS-1 and that this is involved in the regulation of neurite extension and retraction by IGF-1 and TNF-α, respectively. PC12 cells expressing the N-terminal domain show enhanced neurite extension after IGF-1 treatment and reduced neurite depletion relative to control cells after TNF-α treatment. The level of ADAM10 was found to be increased in immunohistochemical studies of HIV encephalitis clinical samples and is present with TNF-α and TNFR1 in both astrocytes and neurons. Altogether, these observations suggest a role for ADAM10 in the mechanism for IGF1/IRS-1 signaling pathway in sustaining the stability of neuronal processes.
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jin Ying
authors.initials: JY
authors.lastname: Wang
authors.forename: Armine
authors.initials: A
authors.lastname: Darbinyan
authors.forename: Martyn K
authors.initials: MK
authors.lastname: White
authors.forename: Nune
authors.initials: N
authors.lastname: Darbinian
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
authors.forename: Shohreh
authors.initials: S
authors.lastname: Amini
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D015658:HIV Infections / Q000150:complications / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000502:physiology*; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; D019012:Integrin beta1; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D008565:Membrane Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C542371:ADAM10 protein, rat; C491234:Adam10 protein, mouse