title: Assessment of downstream effectors of BCR/ABL protein tyrosine kinase using combined proteomic approaches.
abstract: Leukaemic transformation is frequently associated with the aberrant activity of a protein tyrosine kinase (PTK). As such it is of clinical relevance to be able to map the effects of these leukaemogenic PTKs on haemopoietic cells at the level of phosphorylation modulation. In this paradigm study we have employed a range of proteomic approaches to analyse the effects of one such PTK, BCR/ABL. We have employed phosphoproteome enrichment techniques allied to peptide and protein quantification to identify proteins and pathways involved in cellular transformation. Amongst the proteins shown to be regulated at the post-translational level were cofilin, an actin-severing protein thus linked to altered motility and Cbl an E3 ubiquitin ligase integrally linked to the control of tyrosine kinase signalling (regulated by 5 and 6 PTKs respectively). The major class of proteins identified however were molecular chaperones. We also showed that HSP90 phosphorylation is altered by BCR/ABL action and that HSP90 plays a crucial role in oncogene stability. Further investigation with another six leukaemogenic PTKs demonstrates that this HSP90 role in oncogene stability appears to be a common phenomenon in a range of leukaemias. This opens up the potential opportunity to treat different leukaemias with HSP90 inhibitors.
authors: Stem Cell and Leukaemia Proteomics Laboratory, School of Cancer, Enabling Sciences, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Withington, Manchester, UK.
authors: Chia Fang
authors: CF
authors: Lee
authors: Stephen
authors: S
authors: Griffiths
authors: Eva
authors: E
authors: Rodríguez-Suárez
authors: Andrew
authors: A
authors: Pierce
authors: Richard D
authors: RD
authors: Unwin
authors: Ewa
authors: E
authors: Jaworska
authors: Caroline A
authors: CA
authors: Evans
authors: Simon
authors: S
authors: J Gaskell
authors: Anthony D
authors: AD
authors: Whetton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D040901:Proteomics; D015398:Signal Transduction
chemical_list: D018841:HSP90 Heat-Shock Proteins; D010750:Phosphoproteins; D016044:Fusion Proteins, bcr-abl