A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

Abstract

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligandindependent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.

<p>Secretory Pathway Kinase <em>FAM20C</em>, a Marker for Glioma Invasion and Malignancy, Predicts Poor Prognosis of Glioma</p>

“…[11][12][13] Kinases have been shown to play important roles in gliomagenesis. [14][15][16] The understanding of kinase-related mechanism will help us to develop a new strategy against glioma.…”

Circular RNA ZNF609 promotes the malignant progression of glioma by regulating miR-1224-3p/PLK1 signaling

“…Glioma is a prevalent intracranial malignancy contributes to considerable cancer-related mortality [6,27]. Meanwhile, it is characterized by insensitive to conventional chemo-radiotherapy [28,29]. CircRNA is a class of noncoding RNA generated from a non-canonical back splicing process, from a covalent bond between 5' and 3' ends of a single-stranded RNA [30][31][32].…”

Trastuzumab treatment in patients with breast cancer is associated with differential expression of the neurotrophic receptor tyrosine kinase receptor NTRK2.

“…Expression of NTRK2 was documented in patient-derived breast cancer murine xenografts, in brain-trophic triple negative breast cancer cell lines, and in brain metastases from patients with breast cancer 8 . Mutations of NTRK2 have been found in pilocytic astrocytomas 9 , and splice variants of NTRK2 deficits in kinase activity have been discovered in gliomas, indicating importance of NTRK2 in human cancers of the brain 10 . Interestingly, one study suggested that HER2 and NTRK2 may be capable of heterodimerizing; phosphorylated NTRK2 was observed at relatively higher levels than total NTRK2 in brain metastatic tissues, and phosphorylated HER2 and phosphorylated NTRK2 were observed at significantly higher levels in HER2+ breast cancers as compared to triple negative breast cancers in a small subset of patient tumors 11 .…”