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| Item Type: | Article |
|---|---|
| Title: | Inactive β(1)-integrin acts as a junctional scaffold for angiopoietin/TIE2/FOXO1 signaling |
| Creators: |
Sipilä, Tuomas, Ponna, Srinivas Kumar, Venkatesha Murthy, Abhinandan, Pink, Anne, Enkavi, Giray, Bohra, Shraman Kumar, Lewna, Klaudia, Ganesh, Keerthana, Liu, Qina, Korhonen, Mirka, Kajander, Tommi, Potente, Michael  ORCID: https://orcid.org/0000-0002-5689-0036, Ivaska, Johanna, Vattulainen, Ilpo, Leppänen, Veli-Matti and Saharinen, Pipsa
|
| Abstract: | The blood and lymphatic vascular systems are regulated by angiopoietin (ANGPT) growth factors, which signal via endothelial TIE receptor tyrosine kinases and integrins. However, mechanistic understanding of how these receptors crosstalk is limited. Here, we show how β(1)-integrin inactivation regulates endothelial ANGPT/TIE2 signaling. By integrating biophysical analyses, X-ray crystallography, size-exclusion chromatography–small-angle X-ray scattering and atomistic molecular dynamics simulations, we show that ANGPT2 binds through its asymmetrically positioned C-terminal fibrinogen-like domains to both TIE2 and α(5)β(1)-integrin, forming a trimeric complex compatible with the inactive α(5)β(1)-integrin conformation. Inactive β(1)-integrin colocalizes with ANGPT-induced TIE2 in cell-cell junctions and stabilizing β(1)-integrin in its inactive state enhances junctional TIE2 accumulation and promotes nuclear exclusion of the TIE2 transcriptional effector FOXO1 in cultured endothelial cells. Endothelial-specific β(1)-integrin deletion in adult mice reduces venous TIE2 phosphorylation, whereas endotoxemia diminishes junctional β(1)-integrin along with decreased phosphorylated TIE2. In contrast, without TIE2, ANGPT2 uniquely engages active β(1)-integrin, via its N-terminal superclustering domain. Altogether, our results provide structural and mechanistic evidence of ANGPT signaling via α(5)β(1)-integrin and support a model in which inactive α(5)β(1)-integrin acts as a junctional scaffold for ANGPT/TIE2/FOXO1 signaling, explaining how integrin conformational switching spatially organizes growth factor signaling in the endothelium. |
| Keywords: | Angiopoietin-2, Animals, Forkhead Box Protein O1, Integrin Alpha5Beta1, Integrin Beta1, Intercellular Junctions, Knockout Mice, Mice, Signal Transduction, TIE-2 Receptor |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 136 |
| Number: | 12 |
| Page Range: | e190552 |
| Date: | 15 June 2026 |
| Official Publication: | https://doi.org/10.1172/jci190552 |
| PubMed: | View item in PubMed |
| Related to: |
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