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Int J Biochem Cell Biol. 2015 Feb;59:11-20. doi: 10.1016/j.biocel.2014.11.017. Epub 2014 Dec 5.

The immune receptor Tim-3 mediates activation of PI3 kinase/mTOR and HIF-1 pathways in human myeloid leukaemia cells.

Author information

1
School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
2
Institute for Research in Biomedicine, Via Vela 6, 6500 Bellinzona, Switzerland.
3
School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK; High School of Life Sciences, University of Applied Sciences North-Western Switzerland, Muttenz, Switzerland.
4
High School of Life Sciences, University of Applied Sciences North-Western Switzerland, Muttenz, Switzerland; Department of Biomedicine, University of Basel and University Hospital Basel, CH-4031 Basel, Switzerland. Electronic address: e.fasler@unibas.ch.
5
Institute for Research in Biomedicine, Via Vela 6, 6500 Bellinzona, Switzerland. Electronic address: luca.varani@irb.usi.ch.
6
School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK. Electronic address: V.Sumbayev@kent.ac.uk.

Abstract

The T-cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated protein that is highly expressed in human acute myeloid leukaemia cells. As an acute myeloid leukaemia antigen, it could therefore be considered as a potential target for immune therapy and highly-specific drug delivery. However, a conceptual understanding of its biological role is required before consideration of this protein for therapeutic settings. Here, we reveal the detailed mechanism of action underlying the biological responses mediated by the Tim-3 receptor in myeloid cells. Our studies demonstrate that Tim-3 triggers growth factor type responses in acute myeloid leukaemia cells by activating a phosphatidylinositol-3 kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway. In addition, the receptor activates hypoxic signalling pathways upregulating glycolysis and pro-angiogenic responses. These findings suggest that Tim-3 could be used as a potential therapeutic target for immune therapy and drug delivery in human acute myeloid leukaemia cells.

KEYWORDS:

HIF-1; Mammalian target of rapamycin (mTOR) pathway; Myeloid leukaemia cells; Tim-3

PMID:
25483439
DOI:
10.1016/j.biocel.2014.11.017
[Indexed for MEDLINE]

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