THOC5 spliceosome protein: a target for leukaemogenic tyrosine kinases that affects inositol lipid turnover.
The fusion protein TEL/PDGFRB is associated with chronic myelomonocytic leukaemia and has intrinsic tyrosine kinase activity. The effects of TEL/PDGFRB were assessed using the multipotent haemopoietic cell line FDCP-Mix. In the absence of growth factors, TEL/PDGFRB expression increased survival that was associated with elevated levels of phosphatidylinositol 3,4,5 trisphosphate (PIP3). Whilst TEL/PDGFRB had subtle effects on the growth factor requirements it had a profound effect on differentiation. The cells became refractory to cytokine-stimulated development, showing limited maturation but failing to produce fully mature cells. We have previously identified the spliceosome protein THOC5 as a target in macrophage colony-stimulating factor signalling and a protein involved in the regulation of transcription factor expression. TEL/PDGFRB expression increased the expression and phosphorylation of THOC5. Elevated expression of THOC5 increased PIP3 levels and decreased apoptosis. Mass spectrometry was used to identify a site for TEL/PDGFRB-mediated phosphorylation on THOC5, which was shown to be a target for a number of other leukaemogenic tyrosine kinases. Thus, THOC5 is a novel target for modulation of signal transduction with a potential role in leukaemogenesis.
Pierce
Andrew
A
Stem Cell and Leukaemia Proteomics Laboratory, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
Carney
Louise
L
Hamza
Hajja G
HG
Griffiths
John R
JR
Zhang
Liqun
L
Whetton
Beth A
BA
Gonzalez Sanchez
M Belen
MB
Tamura
Teruko
T
Sternberg
David
D
Whetton
Anthony D
AD
D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology
D006133:Growth Substances; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D018129:Phosphatidylinositol Phosphates; C120888:TEL-PDGFRbeta fusion protein, human; C530378:THOC5 protein, human; C060974:phosphatidylinositol 3,4,5-triphosphate; D007294:Inositol