Truncated ALK derived from chromosomal translocation t(2;5)(p23;q35) binds to the SH3 domain of p85-PI3K

Polgar, Doris; Leisser, Christina; Maier, Susanne; Strasser, Stephen; Rüger, Beate M.; Dettke, Markus; Khorchide, Maya; Simonitsch, Ingrid; Cerni, Christa; Krupitza, Georg

doi:10.1016/j.mrfmmm.2004.09.011

Cited by 23 publications

(23 citation statements)

References 18 publications

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“…8,[154][155][156] Activated ALK is involved in the inhibition of apoptosis and the promotion of cellular proliferation through activation of downstream PIK3CA/AKT1-and MAPK1-signaling pathways. 157 Fusion of the EML4-ALK gene and its associated EML4-ALK product may further lead to constitutive activation of the RAS/RAF1/MAP2K1/MAPK1 pathway. 54 Additionally, two other less frequent ALK fusions in lung cancer have been reported, but not yet studied for their downstream consequences.…”

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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“…ALK displays the classical structural features of a receptor tyrosine kinase. In the previous studies, ALK mediated several signaltransduction pathways, including JAK/STAT, RAS/MAPK, PI3K and PLCg, and modulated various cellular functions, such as proliferation, angiogenesis, metabolism and migration 63,64 . An important role of ALK in the development and function of the nervous system has also been reported 65 .…”

Section: Discussionmentioning

confidence: 95%

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

et al. 2014

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Lentiviral short hairpin RNA (shRNA)-mediated genetic screening is a powerful tool for identifying loss-of-function phenotype in mammalian cells. Here, we report the identification of 91 cell migration-regulating genes using unbiased genome-wide functional genetic selection. Individual knockdown or cDNA overexpression of a set of 10 candidates reveals that most of these cell migration determinants are strongly dependent on the PI3K/PTEN/ AKT pathway and on their downstream signals, such as FOXO1 and p70S6K1. ALK, one of the cell migration promoting genes, uniquely uses p55g regulatory subunit of PI3K, rather than more common p85 subunit, to trigger the activation of the PI3K-AKT pathway. Our method enables the rapid and cost-effective genome-wide selection of cell migration regulators. Our results emphasize the importance of the PI3K/PTEN/AKT pathway as a point of convergence for multiple regulators of cell migration.

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“…Therefore, we considered the effect of the N. lobata extract on NPM/ALK suppression as being specific. NPM/ALK was reported to permanently activate Akt via PI3K (30,31). The western blot analysis of untreated control cells showed a low constitutive Akt serine 473 phosphorylation level, which further and transiently decreased upon treatment with N. lobata extract.…”

Section: N Lobata Extract Induces Tumor Suppressors and Inhibits Oncmentioning

confidence: 99%

The dichloromethane extract of the ethnomedicinal plant Neurolaena lobata inhibits NPM/ALK expression which is causal for anaplastic large cell lymphomagenesis

Unger

Popescu

Giessrigl

et al. 2012

International Journal of Oncology

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Abstract. The present study investigates extracts of Neuolaena lobata, an anti-protozoan ethnomedicinal plant of the Maya, regarding its anti-neoplastic properties. Firstly, extracts of increasing polarity were tested in HL-60 cells analyzing inhibition of cell proliferation and apoptosis induction. Secondly, the most active extract was further tested in anaplastic large cell lymphoma (ALCL) cell lines of human and mouse origin. The dichloromethane extract inhibited proliferation of HL-60, human and mouse ALCL cells with an IC 50 of ~2.5, 3.7 and 2.4 µg/ml, respectively and arrested cells in the G2/M phase. The extract induced the checkpoint kinases Chk1 and Chk2 and perturbed the orchestrated expression of the Cdc25 family of cell cycle phosphatases which was paralleled by the activation of p53, p21 and downregulation of c-Myc. Importantly, the expression of NPM/ALK and its effector JunB were drastically decreased, which correlated with the activation of caspase 3. Subsequently also platelet derived growth factor receptor β was downregulated, which was recently shown to be transcriptionally controlled by JunB synergizing with ALK in ALCL development. We show that a traditional healing plant extract downregulates various oncogenes, induces tumor suppressors, inhibits cell proliferation and triggers apoptosis of malignant cells. The discovery of the 'Active Principle(s)' is warranted.

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Truncated ALK derived from chromosomal translocation t(2;5)(p23;q35) binds to the SH3 domain of p85-PI3K

Cited by 23 publications

References 18 publications

Molecular pathology of lung cancer: key to personalized medicine

Molecular pathology of lung cancer: key to personalized medicine

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

The dichloromethane extract of the ethnomedicinal plant Neurolaena lobata inhibits NPM/ALK expression which is causal for anaplastic large cell lymphomagenesis

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