Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation.
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.
Pierce
Andrew
A
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester, UK.
Lu
Yuning
Y
Hamzah
Hajja G
HG
Thompson
Suzanne
S
Owen-Lynch
P J
PJ
Whetton
Anthony D
AD
Spooncer
Elaine
E
D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D015398:Signal Transduction; D014162:Transfection
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D015514:Oncogene Proteins, Fusion; D018129:Phosphatidylinositol Phosphates; C120888:TEL-PDGFRbeta fusion protein, human; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl