title: Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent.
abstract: Genetic abnormalities that result in expression of chimeric tyrosine kinase proteins such as BCR-ABL1 and ETV6-PDGFRbeta 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-PDGFRalpha fusion tyrosine kinase was recently identified as a cause of chronic eosinophilic leukemia. In this report, we demonstrate that FIP1L1 is completely dispensable for PDGFRalpha activation in vitro and in vivo. Instead, truncation of PDGFRalpha between two conserved tryptophan residues in the juxtamembrane (JM) domain is required for kinase activation and transforming potential of FIP1L1-PDGFRalpha. The presence of a complete JM domain in FIP1L1-PDGFRalpha is inhibitory, but this autoinhibition can be overcome by enforced homodimerization. Similar effects of the JM domain in the context of PDGFRbeta 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.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stover
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Cedric
authors.initials: C
authors.lastname: Folens
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D019281:Dimerization; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000737:chemistry*; D039221:mRNA Cleavage and Polyadenylation Factors / Q000737:chemistry*
chemical_list: C479818:FIP1L1 protein, human; D039221:mRNA Cleavage and Polyadenylation Factors; D020796:Receptor, Platelet-Derived Growth Factor alpha