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β1-integrin controls IGF-1R internalization and intracellular signaling.
Niamh McDermott1, Stephen O'Shea1, Leonie Rieger1
1Cell Biology Laboratory, School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
The Journal of Biological Chemistry
|November 28, 2024
Summary
Phosphorylation of insulin-like growth factor 1 receptor (IGF-1R) at Tyr1250/1251 drives cancer cell migration and is enhanced by β1-integrin (ITGB1) signaling, promoting tumor aggressiveness.
Area of Science:
- Molecular and Cellular Biology
- Cancer Research
- Cell Signaling
Background:
- Insulin-like growth factor 1 receptor (IGF-1R) phosphorylation at C-terminal tail tyrosines (Tyr1250/1251) is linked to cell migration and cancer aggressiveness.
- IGF-1R activity is distinct from insulin receptor due to the presence of these specific tyrosines.
- Adhesion signaling pathways significantly influence receptor localization and activity in cancer cells.
Purpose of the Study:
- To investigate how cell adhesion signaling impacts IGF-1R localization and activity in migratory cancer cells and fibroblasts.
- To elucidate the role of β1-integrin (ITGB1) in regulating IGF-1R stability, internalization, and phosphorylation.
- To determine the contribution of Tyr1250/1251 phosphorylation to IGF-1R's protumorigenic functions.
Main Methods:
- Analysis of IGF-1R localization in triple-negative breast cancer tissues versus nontumor tissues.
- Correlation analysis of IGF-1R and β1-integrin (ITGB1) expression in patient datasets.
- Experimental manipulation of ITGB1 expression in cancer cells and fibroblasts, including the use of IGF-1R mutants (FF and EE).
- In silico modeling to assess the conformational impact of tyrosine mutations on the IGF-1R C-terminal tail.
Main Results:
- IGF-1R is predominantly intracellular in triple-negative breast cancer tissues compared to normal tissues.
- A positive correlation exists between IGF-1R and ITGB1 expression in basal-like breast cancer.
- Suppression of ITGB1 increases IGF-1R stability at the plasma membrane and reduces internalization.
- ITGB1 suppression decreases IGF-1R autophosphorylation and Golgi accumulation in fibroblasts.
- Tyr1250/1251 phosphorylation is essential for ITGB1-mediated IGF-1R internalization.
- IGF-1R Tyr1250/1251Glu (EE) mutant enhances cell migration and colony formation.
Conclusions:
- Tyr1250/1251 phosphorylation of IGF-1R confers unique protumorigenic signaling capabilities.
- β1-integrin (ITGB1) signaling enhances IGF-1R's protumorigenic activity by promoting its internalization.
- The findings highlight a critical interplay between IGF-1R and ITGB1 in driving cancer progression.
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