Abstract
Oncogenic rearrangements of the anaplastic lymphoma kinase (ALK) gene, encoding a receptor type tyrosine kinase, are frequently associated with anaplastic large cell lymphomas. Such rearrangements juxtapose the intracellular domain of ALK to 5'-end sequences belonging to different genes and create transforming fusion proteins. To understand how the oncogenic versions of ALK contribute to lymphomagenesis, it is important to analyze the biological effects and the biochemical properties of this receptor under controlled conditions of activation. To this aim, we constructed chimeric receptor molecules in which the extracellular domain of the ALK kinase is replaced by the extracellular, ligand-binding domain of the epidermal growth factor receptor (EGFR). Upon transfection in NIH 3T3 fibroblasts, the EGFR/ALK chimera was correctly synthesized and transported to the cell surface, where it was fully functional in forming high versus low affinity EGF-binding sites and transducing an EGF-dependent signal intracellularly. Overexpression of the EGFR/ALK chimera in NIH 3T3 was sufficient to induce the malignant phenotype; the appearance of the transformed phenotype was, however, conditionally dependent on the administration of EGF. Moreover, the EGFR/ALK chimera was significantly more active in inducing transformation and DNA synthesis than the wild type EGFR when either was expressed at similar levels in NIH 3T3 cells. Comparative analysis of the biochemical pathways implicated in the transduction of mitogenic signals did not show any increased ability of the EGFR/ALK to phosphorylate PLC-gamma and MAPK compared with the EGFR. On the contrary, EGFR/ALK showed to have a consistently greater effect on phosphatidylinositol 3-kinase activity compared with the EGFR, indicating that this enzyme plays a major role in mediating the mitogenic effects of ALK in NIH 3T3 cells.
Highlights
Oncogenic rearrangements of anaplastic lymphoma kinase (ALK) have been detected with a high frequency in anaplastic large cell lymphoma (ALCL), a subgroup of non-Hodgkin’s lymphoma (4 – 8)
Comparative analysis of the biochemical pathways implicated in the transduction of mitogenic signals did not show any increased ability of the epidermal growth factor receptor (EGFR)/ALK to phosphorylate PLC-␥ and MAPK compared with the EGFR
Results have shown that the EGFR/ALK chimera was efficiently expressed in the transfectants as a 150 –160-kDa protein, and it became heavily phosphorylated on tyrosine in a ligand-dependent manner
Summary
Oncogenic rearrangements of ALK have been detected with a high frequency in anaplastic large cell lymphoma (ALCL), a subgroup of non-Hodgkin’s lymphoma (4 – 8) Over half of these lymphomas are characterized by the chromosomal translocation t(2;5)(p23;q35) that results in the production of an 80-kDa chimeric protein in which the N-terminal region of the nuclear protein nucleophosmin (NPM) [9, 10] is fused to the intracellular region of ALK, including the tyrosine kinase domain [7]. Several other oncogenic rearrangements of ALK have been recently identified in ALCLs, suggesting multiple mechanisms for ALK activation in lymphomagenesis Molecular characterization of such alternative chromosomal translocations have identified the nonmuscle tropomyosin gene, the TRK-fused gene, the 5-aminoimidazole4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) gene, the clathrin chain polypeptide-like gene, and the moesin gene as variant fusion partners with the ALK gene (14 –19). The recent identification of PTN as the ligand for ALK has clearly proved the ability of this receptor to deliver mitogenic signals inside the cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
