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Mutual regulation between IGF-1R and IGFBP-3 in human corneal epithelial cells

Rossella Titone1, Meifang Zhu1, Danielle M Robertson1

  • 1The Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas.

Journal of Cellular Physiology
|August 6, 2018
PubMed

Insights

Insulin-like growth factor type 1 receptor (IGF-1R) and insulin-like growth factor binding protein-3 (IGFBP-3) are mutually regulated to maintain corneal epithelial cell survival under stress, with IGFBP-3 mediating nuclear translocation of IGF-1R.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The insulin-like growth factor type 1 receptor (IGF-1R) is a receptor tyrosine kinase crucial for cellular homeostasis, regulating survival, growth, and proliferation.
  • IGF-1R signaling involves nuclear translocation, SUMOylation, and interaction with IGF-1, but its nuclear accumulation in corneal epithelial cells occurs independently of IGF-1.
  • Understanding IGF-1R's role in corneal epithelial cells is vital for maintaining ocular surface homeostasis.

Purpose of the Study:

  • To investigate the mechanism of IGF-1R nuclear translocation in corneal epithelial cells under serum-free conditions.
  • To elucidate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in IGF-1R nuclear localization and its impact on cell cycle regulation and survival.
  • To determine the reciprocal regulation between IGF-1R and IGFBP-3 and their interplay in cellular stress response.

Main Methods:

  • Utilized cultured corneal epithelial cells under serum-free conditions.
  • Investigated IGF-1R nuclear translocation and SUMOylation (SUMO 1 and SUMO 2/3) in response to growth factor withdrawal.
  • Analyzed the reciprocal regulation between IGF-1R and IGFBP-3, assessing effects on cell cycle and mitochondrial respiration, independent of PI3k/Akt signaling.

Main Results:

  • IGFBP-3 mediates the nuclear translocation of IGF-1R in response to growth factor withdrawal via SUMOylation by SUMO 2/3.
  • IGF-1R and IGFBP-3 exhibit reciprocal regulation, independent of PI3k/Akt signaling.
  • Under healthy conditions, IGFBP-3 arrests the cell cycle at G0/G1 without affecting mitochondrial respiration; under stress, it maintains nuclear IGF-1R levels.

Conclusions:

  • IGF-1R and IGFBP-3 are mutually regulated, playing critical roles in maintaining corneal epithelial cell survival during stress.
  • IGFBP-3 acts as a gatekeeper for cell cycle arrest under normal conditions and a caretaker for nuclear IGF-1R levels during stress.
  • This study establishes a direct relationship between IGF-1R and IGFBP-3 in preserving corneal epithelial homeostasis.
Keywords:
SUMOcorneaepitheliuminsulininsulin-like growth factor binding protein-3 (IGFBP-3)insulin-like growth factor type 1 receptor (IGF-1R)

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