| p62dok was first identified as a hyperphosphorylated 62kDa protein, which associates with RasGAP, in patient blasts of Chronic Myeloid Leukemia (CML) and p210bcr-abl-transformed hematopoietic cells. This molecule turned out to be the long sought 62kDa protein phosphorylated upon activation of various receptor tyrosine kinases, antigen receptors, and cytoplasmic tyrosine kinases. p62dok contains an N-terminal PH domain, a central PTB domain, and multiple tyrosines and PXXP motifs which are mainly located in the C-terminus. Besides RasGAP, phosphorylated p62 dok was found to bind NCK and CSK as well. Although p62dok was suggested to serve as an adapter protein recruiting multiple signaling molecules, its biological function(s) remained to be resolved. I obtained evidence indicating that p62dok functions as a negative regulator of growth factor-induced cell proliferation, and that it does so likely through negatively regulating the Ras-MAPK pathway. I further examined the underlying mechanism(s) and demonstrated that in response to PDGF, p62 dok is recruited to the plasma membrane through the binding of its PH domain to the lipid products of PI3-kinase. Such subcellular translocation is essential for p62dok to negatively influence PDGF-triggered MAPK activity. Nonetheless, I found that the association of p62dok with either RasGAP and NCK, or CSK alone, is dispensable for the negative effect of p62dok on MAPK activation. In addition, collaborating with Dr. Pier Paolo Pandolfi, we observed that loss of p62 dok accelerates leukemogenesis induced by p210bcr-abl while ectopic expression of p62dok suppresses p210bcr-abl -triggered transformation. Although it remains unknown as to how p62 dok interferes with p210bcr-abl signaling, these findings suggest that p62dok also acts as a negative regulator of p210 bcr-abl-induced transformation. Finally, I made use of microarray assays to identify p210bcr-abl-regulated genes. The preliminary data will help further our understanding of the molecular mechanism(s) underlying the negative role p62dok plays in CML, as well as the disease in general. |
