title: Nuclear targeting of IGF-1 receptor in orbital fibroblasts from Graves' disease: apparent role of ADAM17.
abstract: Insulin-like growth factor-1 receptor (IGF-1R) comprises two subunits, including a ligand binding domain on extra- cellular IGF-1Rα and a tyrosine phosphorylation site located on IGF-1Rβ. IGF-1R is over-expressed by orbital fibroblasts in the autoimmune syndrome, Graves' disease (GD). When activated by IGF-1 or GD-derived IgG (GD-IgG), these fibroblasts produce RANTES and IL-16, while those from healthy donors do not. We now report that IGF-1 and GD-IgG provoke IGF-1R accumulation in the cell nucleus of GD fibroblasts where it co-localizes with chromatin. Nuclear IGF-1R is detected with anti-IGF-1Rα-specific mAb and migrates to approximately 110 kDa, consistent with its identity as an IGF-1R fragment. Nuclear IGF-1R migrating as a 200 kDa protein and consistent with an intact receptor was undetectable when probed with either anti-IGF-1Rα or anti-IGF-1Rβ mAbs. Nuclear redistribution of IGF-1R is absent in control orbital fibroblasts. In GD fibroblasts, it can be abolished by an IGF-1R-blocking mAb, 1H7 and by physiological concentrations of glucocorticoids. When cell-surface IGF-1R is cross-linked with (125)I IGF-1, (125)I-IGF-1/IGF-1R complexes accumulate in the nuclei of GD fibroblasts. This requires active ADAM17, a membrane associated metalloproteinase, and the phosphorylation of IGF-1R. In contrast, virally encoded IGF-1Rα/GFP fusion protein localizes equivalently in nuclei in both control and GD fibroblasts. This result suggests that generation of IGF-1R fragments may limit the accumulation of nuclear IGF-1R. We thus identify a heretofore-unrecognized behavior of IGF-1R that appears limited to GD-derived fibroblasts. Nuclear IGF-1R may play a role in disease pathogenesis.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, California, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Hoa
authors.forename: Shanli
authors.initials: S
authors.lastname: Tsui
authors.forename: Nikoo F
authors.initials: NF
authors.lastname: Afifiyan
authors.forename: Amiya
authors.initials: A
authors.lastname: Sinha Hikim
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Douglas
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Smith
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism; D006111:Graves Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019410:Interleukin-16 / Q000378:metabolism; D009915:Orbit / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
chemical_list: D018946:Chemokine CCL5; D002843:Chromatin; D005938:Glucocorticoids; D007074:Immunoglobulin G; D019410:Interleukin-16; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human