Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation.

Pierce, Andrew and Lu, Yuning and Hamzah, Hajja G. and Thompson, Suzanne and Owen-Lynch, P. Jane and Whetton, Anthony D. and Spooncer, Elaine (2006) Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation. British Journal of Haematology, 133 (3). pp. 345-352. ISSN 0007-1048

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The chemokine, stromal cell-derived factor-1 (SDF-1) is a crucial regulator of stem cell homing and tethering, and potentiation of this pathway in leukaemias may contribute to the pathogenesis of the disease. A key second messenger in SDF-1 signal/response coupling is phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]. SDF-1 elevated PtdIns(3,4,5)P3 levels markedly in the multipotent FDCP-mix stem cell line. Similarly, transfection with BCR/ABL or TEL/PDGFRβ leukaemogenic tyrosine kinases chronically elevated PtdIns(3,4,5)P3 levels. However, whilst an SDF-1 chemotactic response was observed in TEL/PDGFRβ-transfected cells, in BCR/ABL cells this was markedly decreased, which was not due to Ras-pathway activation. Thus, multipotent cells can respond to SDF-1, despite chronic increases in this second messenger indicating that a discrete pool of SDF-1-stimulated PtdIns(3,4,5)P3 production drives the chemotactic response. To discern the mechanism for the differential effects of these oncogenes we considered subcellular localisation. As TEL/PDGFRβ has a cytosolic location whilst BCR/ABL associates with actin, we removed the actin-binding domain from BCR/ABL. We observed relocation of BCR/ABL to the cytosol and increased SDF-1 responses. We conclude that the localisation of BCR/ABL to the cytoskeleton is essential for effects on motility and moderating SDF-1 responses is not essential in tyrosine kinase-mediated leukaemic transformation.

Item Type: Journal Article
Journal or Publication Title: British Journal of Haematology
Uncontrolled Keywords: /dk/atira/pure/researchoutput/libraryofcongress/qh301
Departments: Faculty of Science and Technology > Lancaster Environment Centre
Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 9249
Deposited By: Dr P Jane Owen-Lynch
Deposited On: 03 Jun 2008 08:57
Refereed?: Yes
Published?: Published
Last Modified: 01 Jan 2020 07:18
URI: https://eprints.lancs.ac.uk/id/eprint/9249

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