Activation Of Signaling Pathways

As a result of the constitutive tyrosine kinase activity, multiple substrates are tyrosine phosphorylated in Bcr-Abl-positive cells, including the oncoprotein itself. As mentioned above, Bcr-Abl has several functional domains that are capable of binding other proteins in tyrosine-dependent and -independent manners. Additional binding sites are generated by autophos-phorylation. The net result is a multiprotein complex held together by multiple protein-protein interactions.8586 In addition, Bcr-Abl phosphorylates a host of substrates that are not directly bound to the protein but impact on crucial cellular functions. Examples include adhesion protein like paxillin and tensin or the focal adhesion kinase (reviewed in Ref. 36).

Research over the past two decades has revealed that multiple signaling pathways are activated in Bcr-Abl-transformed cells. This includes the Ras/Raf/mito-gen-activated kinase pathway,87 phosphatidyl inositol 3 kinase (PI3 kinase),88 STAT5,89 Myc90, and many others (reviewed in Refs. 36,91). Overall, there is extensive redundancy. For example, Ras may be activated in two different ways. One possibility is binding of the adapter protein Grb-2 to phosphorylated tyrosine 177 that subsequently binds and activates the GTP exchange factor Sos, which in turn stabilizes Ras in the active GTP-bound form.92 The second option is activation via the adapter protein Shc, which requires the Abl SH2 domain but not tyrosine 177.93 Studies in cell lines frequently indicated important or even essential functions for individual pathways, suggesting that the respective pathways may be attractive therapeutic targets. However, data obtained in murine models of Bcr-Abl-positive leukemia that employed knockout animals to test for the requirement of certain signaling components in vivo were usually less convincing. For example, the induction of a myeloproliferative syndrome in mice is not impaired in animals with a homozygous deletion of the STAT5A and STAT5B genes94 or the inter leukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor genes.95 Although the rather aggressive phenotype of the murine CML models raises the question whether more subtle effects would be detectable with a model that is closer to the clinical disease, these observations support the view that the redundancy within the signaling network of Bcr-Abl-transformed cells may compensate for the loss of individual components.

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