Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation
Andrew Pierce,
Yuning Lu,
Hajja G. Hamzah,
Suzanne Thompson,
P. J. Owen-Lynch,
Anthony D. Whetton,
Elaine Spooncer,
Andrew Pierce
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorYuning Lu
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorHajja G. Hamzah
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorSuzanne Thompson
Department of Biological Sciences, IENS, University of Lancaster, Bailrigg, Lancaster
Search for more papers by this authorP. J. Owen-Lynch
Department of Biological Sciences, IENS, University of Lancaster, Bailrigg, Lancaster
Search for more papers by this authorAnthony D. Whetton
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorElaine Spooncer
Department of Biomolecular Sciences, UMIST, Manchester, UK
Search for more papers by this authorAndrew Pierce,
Yuning Lu,
Hajja G. Hamzah,
Suzanne Thompson,
P. J. Owen-Lynch,
Anthony D. Whetton,
Elaine Spooncer,
Andrew Pierce
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorYuning Lu
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorHajja G. Hamzah
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorSuzanne Thompson
Department of Biological Sciences, IENS, University of Lancaster, Bailrigg, Lancaster
Search for more papers by this authorP. J. Owen-Lynch
Department of Biological Sciences, IENS, University of Lancaster, Bailrigg, Lancaster
Search for more papers by this authorAnthony D. Whetton
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester
Search for more papers by this authorElaine Spooncer
Department of Biomolecular Sciences, UMIST, Manchester, UK
Search for more papers by this authorAnthony D. Whetton, Leukaemia Research Fund Cellular Development Unit, UMIST, PO Box 88, Manchester M60 1QD, UK.
E-mail: [email protected]
Summary
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.
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