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Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation.
Pierce A, Lu Y, Hamzah H, Thompson S, Owen-Lynch P, Whetton A, Spooncer E
Br J Haematol. 2006;133( 3):345-52.
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Abstract
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/PDGFRbeta leukaemogenic tyrosine kinases chronically elevated PtdIns(3,4,5)P3 levels. However, whilst an SDF-1 chemotactic response was observed in TEL/PDGFRbeta-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/PDGFRbeta 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.
Keyword(s)
Animals; Cell Line; Dose-Response Relationship, Drug; Mice; Signal Transduction; Transfection; analysis: Fusion Proteins, bcr-abl; biosynthesis: Phosphatidylinositol Phosphates; drug effects: Chemotaxis; drug effects: Hematopoietic Stem Cells; metabolism: Actins; metabolism: Cell Transformation, Neoplastic; metabolism: Cytoskeleton; metabolism: Leukemia, Myeloid, Chronic; metabolism: Oncogene Proteins, Fusion; pharmacology: Chemokines, CXC; physiology: 1-Phosphatidylinositol 3-Kinase