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

@article{Simonitsch2001TheCT,
  title={The cytoplasmic truncated receptor tyrosine kinase ALK‐ homodimer immortalizes and cooperates with ras in cellular transformation},
  author={Ingrid Simonitsch and Doris Polgar and Michael A. Hajek and Peter Duchek and Barbara Skrzypek and Sandra Fassl and Andrea Lamprecht and Gerlinde Schmidt and Georg Krupitza and Christa Cerni},
  journal={The FASEB Journal},
  year={2001},
  volume={15}
}
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… 
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Oncogenic protein tyrosine kinases
TLDR
The study of ALK fusion proteins has raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies, given that ALK fusions also occur in the mesenchymal tumor known as inflammatory myofibroblastic tumor (IMT).
Anaplastic lymphoma kinase proteins in growth control and cancer
TLDR
Reports of ALK expression in a range of carcinoma‐derived cell lines together with its apparent role as a receptor for PTN and MK, both of which have been implicated in tumourigenesis, raise the possibility that ALK‐mediated signalling could play a role in the development and or progression of a number of common solid tumours.
Molecular and Functional Characterizations of the Association and Interactions between Nucleophosmin-Anaplastic Lymphoma Kinase and Type I Insulin-Like Growth Factor Receptor 1 , 2
TLDR
It is found that the dual mutation of Tyr and Tyr diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration.
Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma kinase and type I insulin-like growth factor receptor.
TLDR
It is found that the dual mutation of Tyr(644) and Tyr(664) diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin.
TLDR
The data demonstrate that NPM-ALK cell content is determined by its interaction with Hsp90 and Hsp70, and suggest that the alteration of such associations can interfere with N PM-ALK function in ALCL cells.
Expression of anaplastic lymphoma kinase in non-Hodgkin's lymphomas and other malignant neoplasms. Biological, diagnostic, and clinical implications.
  • M. Wasik
  • Medicine
    American journal of clinical pathology
  • 2002
TLDR
Several lines of experimental evidence indicate that the ectopically expressed ALK is oncogenic in ALK+ TCL by being constitutively active owing to autophosphorylation and by stimulating several critical signal transduction pathways involving phospholipase C-gamma, AKT, and STAT3.
Pathobiology of ALK+ anaplastic large-cell lymphoma.
TLDR
Only 13 years after the identification of NPM-ALK, tremendous progress has been made in understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models.
Differential expression of aurora-A kinase in T-cell lymphomas
TLDR
In insights into the possible importance of Aurora-A overexpression in anaplastic large-cell lymphoma pathogenesis, and also suggest that Aurora- A inhibition could be a potential therapeutic approach for patients with anaplastics large- cell lymphoma.
Pathobiology ofALK anaplastic large-cell lymphoma
TLDR
Only 13 years after the identification of NPM-ALK, tremendous progress has been made in the understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models.
Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma
TLDR
A strong correlation was observed between antitumor response and inhibition of N PM-ALK phosphorylation and induction of apoptosis in tumor tissue, illustrating the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL.
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References

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TLDR
Molecular cloning of cDNAs for both the human and mouse ALK proteins reveal that ALK is a novel receptor protein-tyrosine kinase having a putative transmembrane domain and an extracellular domain and shows the greatest sequence similarity to LTK (leukocyte tyrosine Kinase) whose biological function is presently unknown.
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TLDR
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TLDR
It is proposed that the transforming action of ALK may not be reliant on its nucleolar localization, a hypothesis that may have implications for studies of other proteins involved in oncogenesis that are relocalized after the creation of fusion genes.
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TLDR
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TLDR
The 2;5 chromosomal translocation occurs in most anaplastic large-cell non-Hodgkin's lymphomas arising from activated T lymphocytes to fuse the NPM nucleolar phosphoprotein gene on chromosome 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on chromosome 2p23.
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TLDR
In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK), and unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.
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TLDR
The coding sequence of this cDNA turned out to be virtually identical to that of the fusion cDNA for NPM-anaplastic lymphoma kinase (ALK) previously cloned from the transcript of the gene at the breakpoint of the same translocation.
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TLDR
Results indicate that reliable immunostaining of routine biopsy material for NPM-ALK and ALK proteins is feasible and of diagnostic importance, especially because t(2;5)+ ALCL cases have a good prognosis with appropriate treatment.
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TLDR
The fact that patients with ALK lymphomas experience significantly better overall survival than ALK− ALCL demonstrates further that analysis of ALK expression has important prognostic implications.
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