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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Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines
TLDR
Although the receptor could be shown to be consistently expressed with exclusive specificity in tissues developed from the ectoderm, the results do not support any involvement of ALK in the stimulation of tumorigenic cell growth or differentiation so far, indicating that ALK expression is a physiologic rather than a pathologic phenomenon.
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.
Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells.
TLDR
The results illustrate that IL-9/Jak3 signaling plays a significant role in the pathogenesis of ALK+ ALCL and that it represents a potential therapeutic target for treating patients with ALK+, anaplastic large-cell lymphoma.
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.
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References

SHOWING 1-10 OF 67 REFERENCES
Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system
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.
Expression of the ALK tyrosine kinase gene in neuroblastoma.
Nucleophosmin-Anaplastic Lymphoma Kinase of Large-Cell Anaplastic Lymphoma Is a Constitutively Active Tyrosine Kinase That Utilizes Phospholipase C-γ To Mediate Its Mitogenicity
TLDR
PLC-γ is an important downstream target of NPM-ALK that contributes to its mitogenic activity and is likely to be important in the molecular pathogenesis of large-cell anaplastic lymphomas.
Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase is not required for malignant transformation.
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.
Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.
TLDR
The activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
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.
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
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.
Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5).
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.
Biochemical detection of novel anaplastic lymphoma kinase proteins in tissue sections of anaplastic large cell lymphoma.
Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1.
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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