Projects per year
Abstract
Neutrophils are abundant circulating leukocytes that are rapidly recruited to sites of inflammation in an integrin-dependent fashion. Contrasting with the well-characterized regulation of integrin activation, mechanisms regulating integrin inactivation remain largely obscure. Using mouse neutrophils, we demonstrate in this study that the GTPase activating protein ARAP3 is a critical regulator of integrin inactivation; experiments with Chinese hamster ovary cells indicate that this is not restricted to neutrophils. Specifically, ARAP3 acts in a negative feedback loop downstream of PI3K to regulate integrin inactivation. Integrin ligand binding drives the activation of PI3K and of its effectors, including ARAP3, by outside-in signaling. ARAP3, in turn, promotes localized integrin inactivation by negative inside-out signaling. This negative feedback loop reduces integrin-mediated PI3K activity, with ARAP3 effectively switching off its own activator, while promoting turnover of substrate adhesions. In vitro, ARAP3-deficient neutrophils display defective PIP3 polarization, adhesion turnover, and transendothelial migration. In vivo, ARAP3-deficient neutrophils are characterized by a neutrophil-autonomous recruitment defect to sites of inflammation.
Original language | English |
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Pages (from-to) | 1579-1588 |
Journal | The Journal of Immunology |
Volume | 203 |
Issue number | 6 |
Early online date | 19 Aug 2019 |
DOIs | |
Publication status | Published - 15 Sept 2019 |
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Dive into the research topics of 'A Negative Feedback Loop Regulates Integrin Inactivation and Promotes Neutrophil Recruitment to Inflammatory Sites'. Together they form a unique fingerprint.Projects
- 3 Finished
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BBSRC Case Studentship Melina Michael
Vermeren, S. (Principal Investigator) & Hansen, C. (Co-investigator)
2/10/17 → 1/02/22
Project: Research
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Dual Function of the GTPase activating protein ARAP3 in the regulation of endothelial permeability
Vermeren, S. (Principal Investigator), Caporali, A. (Co-investigator) & Rossi, A. (Co-investigator)
1/10/17 → 30/03/21
Project: Research
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The role of cyclin-dependent kinase-9 inhibition in promoting the resolution of chronic inflammation
Rossi, A. (Principal Investigator) & Haslett, C. (Co-investigator)
1/05/13 → 30/10/19
Project: Research