Research output: Contribution to journal › Article › peer-review
Garth L. Burn, Georgina H. Cornish, Katarzyna Potrzebowska, Malin Samuelsson, Juliette Griffié, Sophie Minoughan, Mark Yates, George Ashdown, Nicolas Pernodet, Vicky L. Morrison, Cristina Sanchez-Blanco, Harriet Purvis, Fiona Clarke, Rebecca J. Brownlie, Timothy J. Vyse, Rose Zamoyska, Dylan M. Owen, Lena M. Svensson, Andrew P. Cope
Original language | English |
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Article number | ra99 |
Journal | Science Signaling |
Volume | 9 |
Issue number | 448 |
Early online date | 4 Oct 2016 |
DOIs | |
Accepted/In press | 16 Sep 2016 |
E-pub ahead of print | 4 Oct 2016 |
Published | 4 Oct 2016 |
Additional links |
Superresolution imaging of the cytoplasmic_BURN_Accepted 16September2016_GREEN AAM
SciSignal_manuscript_Cope_et_al.pdf, 291 KB, application/pdf
Uploaded date:12 Sep 2016
Version:Accepted author manuscript
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 auto-immunity in humans in which disease susceptibility is underpinned by inherited phosphatase mutations that perturb integrin function. 2016
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