Interestingly, several studies have revealed a mechanistic intricacy of PDGFRb signaling beyond a simple relationship of dimerization and cross phosphorylation. There is evidence that PDGF activated mitogenic responses and receptor tyrosine phosphoryla tion do not always correlate. The present study shows that unlike the prototypical mechanism underlying GPCR RTK transactivation, DRD4 PDGFRb ERK1/2 signaling does not involve a para crine component, nor does it require PDGFRb cross phos phorylation and dimerization. This suggests that PDGFRb can act as a monomeric scaffold to transmit DRD4 mediated signals, in a tyrosine phosphorylation indepen dent manner. We have recently demonstrated that DRD4 is able to transactivate immaturely glycosylated PDGFRb, which is intracellularly localized.

These findings pre clude the involvement of an extracellular ligand mediated mechanism of PDGFRb activation, and would allow DRD4 to remain engaged in the ERK1/2 signaling pathway, despite desensitization of plasma membrane expressed PDGFRb. The actual mechanism of how DRD4 stimula tion induces PDGFRb transactivation is still unknown, but we speculate that it involves a diffusable factor, such as PI3 kinase, that would be able to act on a monomeric, intracellularly localized PDGFRb. The DRD4 PDGFRb ERK1/2 pathway is distinct from other known forms of transactivation, and so represents a novel system that already has implications in the regulation of downstream effectors such as the NMDA receptor.

Background Expression of the Philadelphia chromosome, result ing from fusion of the non receptor tyrosine kinase ABL1 on chromosome 9 with BCR on chromosome 21, is the hallmark of chronic myeloid leukemia, but is also found Drug_discovery in 20 30% of acute lymphoblastic leukemia cases. The development of clinically applicable tyrosine kinase inhibitors has fundamentally changed the treatment of patients with CML imatinib mesylate induces hematologic remission in nearly all CML patients. In Ph ALL, imatinib is much less effective. Causes for imatinib resistance are the development of cell clones carrying mutations in the kinase domain of BCR ABL1 . low intracellular drug levels caused by disordered expression of influx and efflux transporters . overexpression of BCR ABL1 . and activation of alternative signalling pathways by oncogenic enzymes like v src sarcoma viral oncogene homolog kinases or guanosine triphosphatases.

Many studies performed to elucidate imatinib resis tance have made use of cells ectopically expressing BCR ABL1 or of cell lines which gained resistance after prolonged exposure to rising drug concentrations. Cell lines that were inherently imatinib resistant have rarely been used, which is astonishing because imatinib resistant cell lines KCL 22 and SD 1 were described very early, in 1997. Here, we screened the DSMZ cell lines bank to find imatinib resistant BCR ABL1 positive cell lines.