Novel transcripts reveal a complex structure of the human TRKA gene and imply the presence of multiple protein isoforms

Luberg, Kristi; Park, Rahel; Aleksejeva, Elina; Timmusk, Tõnis

doi:10.1186/s12868-015-0215-x

Cited by 22 publications

(22 citation statements)

References 68 publications

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“…Chromatin immunoprecipitation (ChIP) assays showed ING5 binding the NTRK1 promoter correlated well with NTRK1 transcriptional induction ( Supplementary Figure S3c ), specifically of the variants including an exon highly expressed in the human brain. 62 …”

Section: Resultsmentioning

confidence: 99%

ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways

Wang

Chesnelong

et al. 2017

Oncogene

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Stem cell-like brain tumor initiating cells (BTICs) cause recurrence of glioblastomas, with BTIC ‘stemness’ affected by epigenetic mechanisms. The ING family of epigenetic regulators (ING1-5) function by targeting histone acetyltransferase (HAT) or histone deacetylase complexes to the H3K4me3 mark to alter histone acetylation and subsequently, gene expression. Here we find that ectopic expression of ING5, the targeting subunit of HBO1, MOZ and MORF HAT complexes increases expression of the Oct4, Olig2 and Nestin stem cell markers, promotes self-renewal, prevents lineage differentiation and increases stem cell pools in BTIC populations. This activity requires the plant homeodomain region of ING5 that interacts specifically with the H3K4me3 mark. ING5 also enhances PI3K/AKT and MEK/ERK activity to sustain self-renewal of BTICs over serial passage of stem cell-like spheres. ING5 exerts these effects by activating transcription of calcium channel and follicle stimulating hormone pathway genes. In silico analyses of The Cancer Genome Atlas data suggest that ING5 is a positive regulator of BTIC stemness, whose expression negatively correlates with patient prognosis, especially in the Proneural and Classical subtypes, and in tumors with low SOX2 expression. These data suggest that altering histone acetylation status and signaling pathways induced by ING5 may provide useful clinical strategies to target tumor resistance and recurrence in glioblastoma.

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Section: Resultsmentioning

confidence: 99%

ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways

Wang

Chesnelong

et al. 2017

Oncogene

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“…1 ) [ 19 ]. In human NBs, TrkAIII expression associates with advanced-stage metastatic disease, post-therapeutic relapse and worse prognosis, whereas expression of fully spliced TrkA associates with better prognosis, spontaneous regression and enhanced event-free survival [ 1 , 19 – 22 ]. In addition to NBs, human glioblastoma multiforme tumours also express TrkAIII, including an EGFR and EGFRvIII negative subpopulation, suggesting that TrkAIII represents a potential oncogenic alternative to EGFR and EGFRvIII oncogenes in this tumour type [ 23 ].…”

Section: Trkaiii Detection and Association With Human Malignanciesmentioning

confidence: 99%

“…In contrast to fully spliced TrkA, which exhibits tumour suppressor function in NB and associates with better prognosis, TrkAIII expression associates with advanced stage metastatic disease, post therapeutic relapse and poor prognosis. TrkAIII also induces malignant transformation of NIH3T3 cells and exhibits oncogenic activity in NB models [ 1 , 19 – 22 ], confirming its oncogenic nature and suggesting that patients with tumours that express TrkAIII may benefit from Trk-inhibitory therapy.…”

Section: Introductionmentioning

confidence: 99%

The oncogenic neurotrophin receptor tropomyosin-related kinase variant, TrkAIII

Farina

Cappabianca

Ruggeri

et al. 2018

J Exp Clin Cancer Res

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Oncogenes derived from the neurotrophin receptor tropomyosin-related kinase TrkA act as drivers in sub-populations of a wide-range of human cancers. This, combined with a recent report that both adult and childhood cancers driven by novel oncogenic TrkA chimeric-fusions exhibit profound, long-lived therapeutic responses to the Trk inhibitor Larotrectinib, highlights the need to improve clinical detection of TrkA oncogene-driven cancers in order to maximise this novel therapeutic potential. Cancers potentially driven by TrkA oncogenes include a proportion of paediatric neuroblastomas (NBs) that express the alternative TrkA splice variant TrkAIII, which exhibits exon 6, 7 and 9 skipping and oncogenic-activity that depends upon deletion of the extracellular D4 Ig-like domain. In contrast to fully spliced TrkA, which exhibits tumour suppressor activity in NB and associates with good prognosis, TrkAIII associates with advanced stage metastatic disease, post therapeutic relapse and worse prognosis, induces malignant transformation of NIH-3T3 cells and exhibits oncogenic activity in NB models. TrkAIII induction in NB cells is stress-regulated by conditions that mimic hypoxia or perturbate the ER with potential to change TrkA tumour-suppressing signals into oncogenic TrkAIII signals within the stressful tumour microenvironment. In contrast to cell surface TrkA, TrkAIII re-localises to intracellular pre-Golgi membranes, centrosomes and mitochondria, within which it exhibits spontaneous ligand-independent activation, triggering a variety of mechanisms that promote tumorigenicity and malignant behaviour, which impact the majority of cancer hallmarks. In this review, we present updates on TrkAIII detection and association with human malignancies, the multiple ways TrkAIII exerts oncogenic activity and potential therapeutic approaches for TrkAIII expressing cancers, with particular reference to NB.

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“…Alternative TrkAIII splicing of the neurotrophin receptor gene TrkA in neuroblastoma (NB) is characterised by exon 6–7 skipping, associates with advanced stage metastatic disease and post-therapeutic relapse, and in NB models TrkAIII exhibits oncogenic activity and promotes chemotherapeutic resistance [ 1 – 8 ]. The TrkAIII oncoprotein is devoid of the D4 activation-prevention domain [ 1 , 9 ] and several N-glycosylation sites important for cell surface receptor localisation [ 1 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

TrkAIII signals endoplasmic reticulum stress to the mitochondria in neuroblastoma cells, resulting in glycolytic metabolic adaptation

et al. 2017

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Alternative TrkAIII splicing characterises advanced stage metastatic disease and post-therapeutic relapse in neuroblastoma (NB), and in NB models TrkAIII exhibits oncogenic activity. In this study, we report a novel role for TrkAIII in signaling ER stress to the mitochondria in SH-SY5Y NB cells that results in glycolytic metabolic adaptation. The ER stress-inducing agents DTT, A23187 and thapsigargin activated the ER stress-response in control pcDNA SH-SY5Y and TrkAIII expressing SH-SY5Y cells and in TrkAIII SH-SY5Y cells increased TrkAIII targeting to mitochondria and internalisation into inner-mitochondrial membranes. Within inner-mitochondrial membranes, TrkAIII was subjected to Omi/HtrA2-dependent cleavage to tyrosine phosphorylated 45–48kDa carboxyl terminal active fragments, localised predominantly in tyrosine kinase-domain mitochondrial matrix orientation. This stress-induced activation of mitochondrial TrkAIII was associated with increased ROS production, prevented by the ROS scavenger Resveratrol and underpinned by changes in Ca2+ movement, implicating ROS/Ca2+ interplay in overcoming the mitochondrial TrkAIII activation threshold. Stress-induced, cleavage-activation of mitochondrial TrkAIII resulted in mitochondrial PDHK1 tyrosine phosphorylation, leading to glycolytic metabolic adaptation. This novel mitochondrial role for TrkAIII provides a potential self-perpetuating, drug reversible way through which tumour microenvironmental stress may maintain the metastasis promoting “Warburg effect” in TrkAIII expressing NBs.

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Novel transcripts reveal a complex structure of the human TRKA gene and imply the presence of multiple protein isoforms

Cited by 22 publications

References 68 publications

ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways

ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways

The oncogenic neurotrophin receptor tropomyosin-related kinase variant, TrkAIII

TrkAIII signals endoplasmic reticulum stress to the mitochondria in neuroblastoma cells, resulting in glycolytic metabolic adaptation

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