Nuclear targeting of IGF-1 receptor in orbital fibroblasts from Graves' disease: apparent role of ADAM17

PLoS One. 2012;7(4):e34173. doi: 10.1371/journal.pone.0034173. Epub 2012 Apr 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Chemokine CCL5 / metabolism
  • Chromatin / metabolism
  • Fibroblasts / metabolism*
  • Glucocorticoids / metabolism
  • Graves Disease / metabolism*
  • Graves Disease / pathology
  • Humans
  • Immunoglobulin G / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-16 / metabolism
  • Orbit / cytology
  • Orbit / metabolism*
  • Phosphorylation / physiology
  • Protein Transport / physiology
  • Receptor, IGF Type 1 / metabolism*


  • Chemokine CCL5
  • Chromatin
  • Glucocorticoids
  • Immunoglobulin G
  • Interleukin-16
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human