Evidence that the lipid phosphatase SHIP-1 regulates T lymphocyte morphology and motility

Stephanie J Harris, Richard V Parry, John G Foster, Matthew D Blunt, A Wang, F Marelli-Berg, J Westwick, Stephen G Ward

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

SHIP-1 negatively regulates the PI3K pathway in hematopoietic cells and has an emerging role in T lymphocyte biology. PI3K and SHIP can regulate cell migration in leukocytes, particularly in neutrophils, although their role in T cell migration has been less clear. Therefore, we sought to explore the role of SHIP-1 in human CD4(+) T lymphocyte cell migration responses to chemoattractants using a lentiviral-mediated expression system and a short hairpin RNA approach. Silencing of SHIP-1 leads to increased basal phosphorylation of protein kinase B/Akt and its substrate GSK3 beta, as well as an increase in basal levels of polymerized actin, suggesting that SHIP-1 might regulate changes in the cytoskeleton. Accordingly, silencing of SHIP-1 led to loss of microvilli and ezrin/radixin/moesin phosphorylation, which could not be rescued by the PI3K inhibitor Ly294002. There were striking morphological changes, including a loss of microvilli projections, which mirrored changes in wild type cells after stimulation with the chemokine CXCL11. There was no defect in directional T cell migration toward CXCL11 in the SHIP-1-silenced cells but, importantly, there was a defect in the overall basal motility of SHIP-1 knockdown cells. Taken together, these results implicate SHIP-1 as a key regulator of basal PI3K signaling in human CD4(+) T lymphocytes with important phosphatase-independent actions, which together are key for maintaining normal morphology and basal motility. The Journal of Immunology, 2011, 186: 4936-4945.
Original languageEnglish
Pages (from-to)4936-4945
Number of pages10
JournalThe Journal of Immunology
Volume186
Issue number8
Early online date14 Mar 2011
DOIs
Publication statusPublished - 15 Apr 2011

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