title: Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma.
abstract: Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK(del2-3)) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK(del2-3) was autophosphorylated in NB-1 cells as well as in ALK(del2-3)-transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK(del2-3)-transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK(del2-3)-expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Okubo
authors.forename: J
authors.initials: J
authors.lastname: Takita
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Oki
authors.forename: R
authors.initials: R
authors.lastname: Nishimura
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Sanada
authors.forename: M
authors.initials: M
authors.lastname: Hiwatari
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Igarashi
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D023061:Gene Order; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: C516714:NVP-TAE684; D011743:Pyrimidines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases