Burn, G. L. et al. (2016) Superresolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated T cell adhesion with autoimmunity. Science Signaling, 9(448), ra99. (doi: 10.1126/scisignal.aaf2195) (PMID:27703032)
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Abstract
Integrins are heterodimeric transmembrane proteins that play a fundamental role in the migration of leukocytes to sites of infection or injury. We found that protein tyrosine phosphatase nonreceptor type 22 (PTPN22) inhibits signaling by the integrin lymphocyte function-associated antigen–1 (LFA-1) in effector T cells. PTPN22 colocalized with its substrates at the leading edge of cells migrating on surfaces coated with the LFA-1 ligand intercellular adhesion molecule–1 (ICAM-1). Knockout or knockdown of PTPN22 or expression of the autoimmune disease–associated PTPN22-R620W variant resulted in the enhanced phosphorylation of signaling molecules downstream of integrins. Superresolution imaging revealed that PTPN22-R620 (wild-type PTPN22) was present as large clusters in unstimulated T cells and that these disaggregated upon stimulation of LFA-1, enabling increased association of PTPN22 with its binding partners at the leading edge. The failure of PTPN22-R620W molecules to be retained at the leading edge led to increased LFA-1 clustering and integrin-mediated cell adhesion. Our data define a previously uncharacterized mechanism for fine-tuning integrin signaling in T cells, as well as a paradigm of autoimmunity in humans in which disease susceptibility is underpinned by inherited phosphatase mutations that perturb integrin function.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Morrison, Dr Vicky |
| Authors: | Burn, G. L., Cornish, G. H., Potrzebowska, K., Samuelsson, M., Griffie, J., Minoughan, S., Yates, M., Ashdown, G., Pernodet, N., Morrison, V. L., Sanchez-Blanco, C., Purvis, H., Clarke, F., Brownlie, R. J., Vyse, T. J., Zamoyska, R., Owen, D. M., Svensson, L. M., and Cope, A. P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Science Signaling |
| Publisher: | American Association for the Advancement of Science |
| ISSN: | 1945-0877 |
| ISSN (Online): | 1937-9145 |
| Copyright Holders: | Copyright © 2016 American Association for the Advancement of Science |
| First Published: | First published in Science Signaling 9(448):ra99 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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