Activation of FIP1L1-PDGFR[alpha] requires disruption of the juxtamembrane domain of PDGFR[alpha] and is FIP1L1-independent

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-05, Vol.103 (21), p.8078
• Main Authors: Stover, Elizabeth H, Chen, Jing, Folens, Cedric, Lee, Benjamin H
• Format: Article
• Language: English
• Subjects: Enzymes; Gene expression; Genetic disorders; Leukemia; Proteins
• ISSN: 0027-8424; 1091-6490

Genetic abnormalities that result in expression of chimeric tyrosine kinase proteins such as BCR-ABL1 and ETV6-PDGFRß are common causes of hematopoietic malignancies. The paradigm for constitutive activation of these fusion tyrosine kinases is enforced homodimerization by self-association domains present in the fusion partner proteins. The unique interstitial deletion on chromosome 4q12 that leads to expression of the FIP1L1-PDGFRα fusion tyrosine kinase was recently identified as a cause of chronic eosinophilic leukemia. In this report, we demonstrate that FIP1L1 is completely dispensable for PDGFRα activation in vitro and in vivo. Instead, truncation of PDGFRα between two conserved tryptophan residues in the juxtamembrane (JM) domain is required for kinase activation and transforming potential of FIP1L1-PDGFRα. The presence of a complete JM domain in FIP1L1-PDGFRα is inhibitory, but this autoinhibition can be overcome by enforced homodimerization. Similar effects of the JM domain in the context of PDGFRß were observed. These results suggest that disruption of the autoinhibitory JM domain is an alternative, dimerization-independent mechanism by which chimeric tyrosine kinases are constitutively activated and induce leukemogenesis. [PUBLICATION ABSTRACT]