The cytoplasmic truncated receptor tyrosine kinase ALK‐ homodimer immortalizes and cooperates with ras in cellular transformation

• Published in: The FASEB journal 2001-06, Vol.15 (8), p.1416-1418
• Main Authors: Simonitsch, Ingrid, Polgar, Doris, Hajek, Maria, Duchek, Peter, Skrzypek, Barbara, Fassl, Sandra, Lamprecht, Andrea, Schmidt, Gerlinde, Krupitza, Georg, Cerni, Christa
• Format: Article
• Language: English
• Subjects: Anaplastic Lymphoma Kinase; Animals; Cell Division; Cell Transformation, Neoplastic - genetics; Genes, ras; immortalization; Lymphoma, Large-Cell, Anaplastic - genetics; NPM/ALK; NPM/ALK constructs; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Peptide Fragments; primary rat embryo cells; Protein-Tyrosine Kinases - genetics; Rats; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; transformation; tumor formation
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.00-0678fje

ABSTRACT Anaplastic large‐cell lymphomas are highly associated with a chromosomal translocation t(2;5). This condition results in a chimeric protein NPM/ALK (nucleophosmin/anaplastic lymphoma kinase), in which the shuttle protein NPM is fused to the catalytic domain of the tyrosine receptor kinase ALK. Because the oncogenic potential of NPM/ALK is not well understood, we analyzed the effects of NPM/ALK and the specific contribution of ALK in a standardized cell culture system by using primary rat embryo cells (REC) as cellular targets. We demonstrate by several biological parameters that NPM/ALK is an immortalizing oncogene that provides unlimited, yet normal, growth potential to REC and, with cooperation with a c‐H‐ras oncogene, induces cellular transformation. Targeting NPM/ALK to the nucleus diminishes its oncogenicity, which indicates that the fusion protein exerts its action mainly in the cytoplasm. Expression of the mere catalytic domain of ALK is insufficient with regard to immortalization and transformation. However, reestablishing the potential of ALK to homodimerize by fusing the bacterial dimerization domain of the tetracycline repressor to ALK reenforces the immortalizing function. Collaboration of dimeric ALK with c‐H‐ras converted primary REC into aggressively growing tumor cell lines. These studies identify ALK as a new member of immortalizing oncoproteins that exerts its function within the cytoplasm.