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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Downregulation of the αvβ6 Integrin via RGD Engagement Is Affinity and Time Dependent

James A. Roper, Alex L. Wilkinson, Elaine Gower and Robert J. Slack
Journal of Pharmacology and Experimental Therapeutics February 2021, 376 (2) 273-280; DOI: https://doi.org/10.1124/jpet.120.000379
James A. Roper
Fibrosis Discovery Performance Unit (DPU), Respiratory Therapy Area Unit (TAU), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom
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  • ORCID record for James A. Roper
Alex L. Wilkinson
Fibrosis Discovery Performance Unit (DPU), Respiratory Therapy Area Unit (TAU), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom
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Elaine Gower
Fibrosis Discovery Performance Unit (DPU), Respiratory Therapy Area Unit (TAU), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom
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Robert J. Slack
Fibrosis Discovery Performance Unit (DPU), Respiratory Therapy Area Unit (TAU), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom
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Abstract

The arginyl-glycinyl-aspartic acid (RGD) integrin alpha-v beta-6 (αvβ6) has been identified as playing a key role in the activation of transforming growth factor-β (TGFβ) that is hypothesized to be pivotal in the development of fibrosis and other diseases. In this study, αvβ6 small molecule inhibitors were characterized in a range of in vitro systems to determine affinity, kinetics, and duration of TGFβ inhibition. High αvβ6 binding affinity was shown to be correlated with slow dissociation kinetics. Compound 1 (high αvβ6 affinity, slow dissociation) and SC-68448 (low αvβ6 affinity, fast dissociation) induced concentration- and time-dependent internalization of αvβ6 in normal human bronchial epithelial (NHBE) cells. After washout, the αvβ6 cell surface repopulation was faster for SC-68448 compared with compound 1. In addition, αvβ6-dependent release of active TGFβ from NHBE cells was inhibited by compound 1 and SC-68448. After washout of SC-68448, release of active TGFβ was restored, whereas after washout of compound 1 the inhibition of TGFβ activation was maintained and only reversible in the presence of a lysosomal inhibitor (chloroquine). However, SC-68448 was able to reduce total levels of αvβ6 in NHBE cells if present continuously. These observations suggest αvβ6 can be degraded after high affinity RGD binding that sorts the integrin for lysosomal degradation after internalization, likely due to sustained engagement as a result of slow dissociation kinetics. In addition, the αvβ6 integrin can also be downregulated after sustained engagement of the RGD binding site with low affinity ligands that do not sort the integrin for immediate lysosomal degradation.

SIGNIFICANCE STATEMENT The fate of RGD integrin after ligand binding has not been widely investigated. Using the αvβ6 integrin as a case study, we have demonstrated that RGD-induced downregulation of αvβ6 is both affinity and time dependent. High affinity ligands induced downregulation via lysosomal degradation, likely due to slow dissociation, whereas sustained low affinity ligand engagement was only able to decrease αvβ6 expression over longer periods of time. Our study provides a potential unique mechanism for obtaining duration of action for drugs targeting integrins.

Footnotes

    • Received October 16, 2020.
    • Accepted November 30, 2020.
  • This work received no external funding.

  • This work was previously presented at the following meeting: Gower E, Wilkinson A, and Slack RJ (2017) Downregulation of the αvβ6 integrin can occur via short engagement with high affinity ligands or long engagement with low affinity ligands. British Pharmacological Society (BPS) Pharmacology 2017; 2017 Dec 11–13; London, UK.

  • https://doi.org/10.1124/jpet.120.000379.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

RGD Engagement and Downregulation of αvβ6

James A. Roper, Alex L. Wilkinson, Elaine Gower and Robert J. Slack
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 273-280; DOI: https://doi.org/10.1124/jpet.120.000379

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

RGD Engagement and Downregulation of αvβ6

James A. Roper, Alex L. Wilkinson, Elaine Gower and Robert J. Slack
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 273-280; DOI: https://doi.org/10.1124/jpet.120.000379
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