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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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/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.

Original languageEnglish
Pages (from-to)345-352
Number of pages8
JournalBritish Journal of Haematology
Volume133
Issue number3
DOIs
Publication statusPublished - 1 May 2006
Externally publishedYes

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Chemokine CXCL12
Protein-Tyrosine Kinases
Cell Movement
Second Messenger Systems
Actins
Stem Cells
Cytoskeleton
Oncogenes
Chemokines
Cytosol
Transfection
Leukemia
phosphatidylinositol 3,4,5-triphosphate
Cell Line

Cite this

Pierce, Andrew ; Lu, Yuning ; Hamzah, Hajja G. ; Thompson, Suzanne ; Owen-Lynch, P. J. ; Whetton, Anthony D. ; Spooncer, Elaine. / Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation. In: British Journal of Haematology. 2006 ; Vol. 133, No. 3. pp. 345-352.
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Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation. / Pierce, Andrew; Lu, Yuning; Hamzah, Hajja G.; Thompson, Suzanne; Owen-Lynch, P. J.; Whetton, Anthony D.; Spooncer, Elaine.

In: British Journal of Haematology, Vol. 133, No. 3, 01.05.2006, p. 345-352.

Research output: Contribution to journalArticle

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AU - Lu, Yuning

AU - Hamzah, Hajja G.

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