Phosphoproteomics reveals ALK promote cell progress via RAS/JNK pathway in neuroblastoma

Chen, Kai; Lv, Fan; Xu, Guofeng; Zhang, Min; Wu, Zhixiang

doi:10.18632/oncotarget.12513

Cited by 13 publications

(11 citation statements)

References 49 publications

(59 reference statements)

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“…Analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment confirmed that proteins with down-regulated phosphorylation sites were shared among other canonical RTK signaling pathways (Fig. 3D), in agreement with a previous study (31). In contrast, proteins with up-regulated sites were significantly associated with pathways related to axon guidance, prolactin signaling, regulation of actin cytoskeleton, and signaling related to the FoxO transcription factors (Fig.…”

Section: The Druggable Alk Phosphoproteome Identifies Alk-driven Phossupporting

confidence: 90%

“…S1C) combined with high-resolution liquid chromatography-tandem MS (LC-MS/MS). We reasoned that combining the quantitative proteomics analysis for three ALK-targeting TKIs (TAE684, LDK378, and crizotinib) and analyzing the overlapping effects on ALK signaling would help to control for off-targets and serve as a better readout for ALK signaling inhibition compared to the previously used single-treatment strategy (30,31). Moreover, we performed three triple-SILAC experiments, allowing us to measure the effect of each inhibitor in duplicate to obtain more robust insights into inhibitor-specific effects ( fig.…”

Section: Ipp Refines Aberrant Alk Signaling Network In Nb Cellsmentioning

confidence: 99%

“…A few phosphoproteomics studies have successfully addressed constitutive ALK signaling through an inhibitor-based approach using crizotinib in NSCLC and NB cells (30)(31)(32). However, for NB specifically, the depth of analysis regarding the number of quantified phosphotyrosine sites has been insufficient to capture many of the important regulatory sites (31). Here, we measured the responses of NB cells with ALK Amp to treatment with TAE684, crizotinib, LDK378, and lorlatinib by quantitative proteomics.…”

Section: Introductionmentioning

confidence: 99%

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Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

et al. 2018

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Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry–based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathways. Our integrated proximal proteomics (IPP) strategy included multiple signaling layers, such as the ALK interactome, phosphotyrosine interactome, phosphoproteome, and proteome. We identified the signaling adaptor protein IRS2 (insulin receptor substrate 2) as a major ALK target and an ALK TKI–sensitive signaling node in neuroblastoma cells driven by oncogenic ALK. TKI treatment decreased the recruitment of IRS2 to ALK and reduced the tyrosine phosphorylation of IRS2. Furthermore, siRNA-mediated depletion of ALK or IRS2 decreased the phosphorylation of the survival-promoting kinase Akt and of a downstream target, the transcription factor FoxO3, and reduced the viability of three ALK-driven neuroblastoma cell lines. Collectively, our IPP analysis provides insight into the proximal architecture of oncogenic ALK signaling by revealing IRS2 as an adaptor protein that links ALK to neuroblastoma cell survival through the Akt-FoxO3 signaling axis.

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Section: The Druggable Alk Phosphoproteome Identifies Alk-driven Phossupporting

confidence: 90%

Section: Ipp Refines Aberrant Alk Signaling Network In Nb Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

et al. 2018

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“…However, a phase I clinical trial evaluating the efficacy of crizotinib as a single-agent revealed unfavorable results in neuroblastoma patients [ 109 ]. Therefore, the proportion of ALK-positive neuroblastoma patients benefits from Crizotinib is limited [ 110 – 112 ]. ATRX was found to be mutated in approximately 50% of adolescent and young adults with neuroblastoma [ 28 , 92 ].…”

Section: Promising Therapeutic Targetsmentioning

confidence: 99%

Research progress of neuroblastoma related gene variations

Cao

Jin

et al. 2016

Oncotarget

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Neuroblastoma, the most common extracranial solid tumor among children, is an embryonal tumor originating from undifferentiated neural crest cell. Neuroblastomas are highly heterogeneous, represented by the wide range of clinical presentations and likelihood of cure, ranging from spontaneous regression to relentless progression despite rigorous multimodal treatments. Approximately, 50% of cases are high-risk with overall survival rates less than 40%. With the efforts to collect large numbers of clinically annotated specimens and the advancements in technologies, researchers have revealed numerous genetic alterations that may drive tumor growth. However, the most lack mutations in genes that are recurrently mutated, which inspires researchers to identify disrupted pathways instead of single mutated genes to unearth biological systems perturbed in neuroblastoma. Stratification of patients and target therapy based on their molecular signatures have been the center of focus. This review provides a comprehensive summary of the recent advances in identification of candidate genes variations, targeted approaches to high-risk neuroblastoma and evaluates the methods utilized for detection, which will provide new avenues to develop therapies and further genetic researches.

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“…Phosphoproteomics has also been used to study various oncogenic signaling pathways such as Ras signaling [10] and PI3K signaling [11]. It has been applied to study lung cancer [12,13], ovarian cancer [14], neuroblastoma [15,16], and many other cancer entities.…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells

et al. 2020

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Background: Aberrant hedgehog (HH) signaling is implicated in the development of various cancer entities such as medulloblastoma. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Increased phosphorylation of essential effectors such as Smoothened (SMO) and GLI proteins by kinases including Protein Kinase A, Casein Kinase 1, and Glycogen Synthase Kinase 3 β controls effector activity, stability and processing. However, a deeper and more comprehensive understanding of phosphorylation in the signal transduction remains unclear, particularly during early response processes involved in SMO activation and preceding GLI target gene regulation. Methods: We applied temporal quantitative phosphoproteomics to reveal phosphorylation dynamics underlying the short-term chemical activation and inhibition of early hedgehog signaling in HH responsive human medulloblastoma cells. Medulloblastoma cells were treated for 5.0 and 15 min with Smoothened Agonist (SAG) to induce and with vismodegib to inhibit the HH pathway. Results: Our phosphoproteomic profiling resulted in the quantification of 7700 and 10,000 phosphosites after 5.0 and 15 min treatment, respectively. The data suggest a central role of phosphorylation in the regulation of ciliary assembly, trafficking, and signal transduction already after 5.0 min treatment. ERK/MAPK signaling, besides Protein Kinase A signaling and mTOR signaling, were differentially regulated after short-term treatment. Activation of Polo-like Kinase 1 and inhibition of Casein Kinase 2A1 were characteristic for vismodegib treatment, while SAG treatment induced Aurora Kinase A activity. Distinctive phosphorylation of central players of HH signaling such as SMO, SUFU, GLI2 and GLI3 was observed only after 15 min treatment.

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Phosphoproteomics reveals ALK promote cell progress via RAS/JNK pathway in neuroblastoma

Cited by 13 publications

References 49 publications

Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

Research progress of neuroblastoma related gene variations

Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells

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