Kinase activation and transformation by NUP214-ABL1 is dependent on the context of the nuclear pore.
Genetic alterations causing constitutive tyrosine kinase activation are observed in a broad spectrum of cancers. Thus far, these mutant kinases have been localized to the plasma membrane or cytoplasm, where they engage proliferation and survival pathways. We report that the NUP214-ABL1 fusion is unique among these because of its requisite localization to the nuclear pore complex for its transforming potential. We show that NUP214-ABL1 displays attenuated transforming capacity as compared to BCR-ABL1 and that NUP214-ABL1 preferentially transforms T cells, which is in agreement with its unique occurrence in T cell acute lymphoblastic leukemia. Furthermore, NUP214-ABL1 differs from BCR-ABL1 in subcellular localization, initiation of kinase activity, and signaling and lacks phosphorylation on its activation loop. In addition to delineating an unusual mechanism for kinase activation, this study provides new insights into the spectrum of chromosomal translocations involving nucleoporins by indicating that the nuclear pore context itself may play a central role in transformation.
De Keersmaecker
Kim
K
Department of Molecular and Developmental Genetics, VIB, K.U. Leuven, Leuven 3000, Belgium.
Rocnik
Jennifer L
JL
Bernad
Rafael
R
Lee
Benjamin H
BH
Leeman
Dena
D
Gielen
Olga
O
Verachtert
Hanne
H
Folens
Cedric
C
Munck
Sebastian
S
Marynen
Peter
P
Fornerod
Maarten
M
Gilliland
D Gary
DG
Cools
Jan
J
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D022022:Nuclear Pore / Q000201:enzymology*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
C521114:NUP214-ABL1 fusion protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases