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Analysis of the cellular uptake and nuclear delivery of insulin-like growth factor binding protein-3 in human
Lucia Micutkova1, Martin Hermann, Martin Offterdinger
1Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria.
Abstract:
Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) regulates cell proliferation and survival by extracellular interaction and inactivation of the growth factor IGF-I. Beyond that, IGF-independent actions mediated by intracellular IGFBP-3 including nuclear-IGFBP-3, have also been described. We here show, using both confocal and electron microscopy and cell fractionation, that the extracellular addition of IGFBP-3 to living cells results in rapid uptake and nuclear delivery of IGFBP-3, by yet partly unknown mechanisms. IGFBP-3 is internalized through a dynamin-dependent pathway, traffics through endocytic compartments and is finally delivered into the nucleus. We observed docking of IGFBP-3 containing structures to the nuclear envelope and found IGFBP-3 containing dot-like structures to permeate the nuclear envelope. In summary, our findings establish the pathway by which this tumor suppressor protein is delivered from extracellular space to the nucleus.
Insights
Extracellular Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is rapidly internalized by cells and delivered to the nucleus. This study elucidates the pathway for nuclear transport of IGFBP-3, a key tumor suppressor.
Area of Science:
- Cell biology
- Molecular biology
- Cancer research
Background:
- Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is known to regulate cell proliferation and survival through extracellular mechanisms involving IGF-I.
- Intracellular and nuclear functions of IGFBP-3, independent of IGF-I, have also been reported, suggesting a complex role in cellular processes.
Purpose of the Study:
- To investigate the mechanism and pathway of extracellular IGFBP-3 uptake and nuclear delivery in living cells.
- To elucidate the cellular journey of IGFBP-3 from the extracellular environment to the nucleus.
Main Methods:
- Confocal microscopy
- Electron microscopy
- Cell fractionation techniques
- Dynamin-dependent pathway analysis
Main Results:
- Extracellular IGFBP-3 is rapidly internalized by cells via a dynamin-dependent pathway.
- Internalized IGFBP-3 traffics through endocytic compartments before reaching the nucleus.
- IGFBP-3 containing structures were observed to dock with and permeate the nuclear envelope.
Conclusions:
- This study establishes the pathway for the delivery of extracellular IGFBP-3 to the nucleus.
- Understanding this pathway is crucial for comprehending the nuclear functions of IGFBP-3 as a tumor suppressor protein.
