• Molecules and Cells
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• v.26 no.1
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• pp.12-17
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• 2008

The TrkA tyrosine kinase is activated by autophosphorylation in response to NGF, and plays an important role in cell survival, differentiation, and apoptosis. To investigate its role in cell fate determination, we produced stable TrkA-inducible SK-N-MC and U2OS cell lines using the Tet-On system. Interestingly, TrkA overexpression induced substantial cell death even in the absence of NGF, by stimulating ERK phosphorylation and caspase-7 activation leading to PARP cleavage. TrkA-mediated cell death was shown by the annexin-V binding assay to be, at least in part, apoptotic in both SK-N-MC and U2OS cells. Furthermore, the truncated form (p18) of Bax accumulated in the TrkA-induced cells, suggesting that TrkA induces mitochondria-mediated apoptosis. NGF treatment augmented the cell death induced by TrkA overexpression. This TrkA-induced cell death was blocked by the tyrosine kinase inhibitors, K-252a and GW441756. Moreover, TrkA overexpression inhibited long-term proliferation of both the neuronal SK-N-MC cells and the non-neuronal U2OS cells, suggesting a potential role of TrkA as a tumor suppressor.

• BMB Reports
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• v.44 no.3
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• pp.182-186
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• 2011

Exogenous stimuli such as nerve growth factor (NGF) exert their effects on neurite outgrowth via Trk neurotrophin receptors. TrkA receptors are known to be ubiquitinated via proteasome inhibition in the presence of NGF. However, the effect of proteasome inhibition on neurite outgrowth has not been studied extensively. To clarify these issues, we investigated signaling events in PC12 cells treated with NGF and the proteasome inhibitor MG132. We found that MG132 facilitated NGF-induced neurite outgrowth and potentiated the phosphorylation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways and TrkA receptors. MG132 stimulated internalization of surface TrkA receptor and stabilized intracellular TrkA receptor, and the $Ub^{K63}$ chain was found to be essential for stability. These results indicate that the ubiquitin-proteasome system potentiated neurite formation by regulating the stability of TrkA receptors.

• Molecules and Cells
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• v.39 no.3
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• pp.258-265
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• 2016

In metastatic breast cancer, the acquisition of malignant traits has been associated with the increased rate of cell growth and division, mobility, resistance to chemotherapy, and invasiveness. While screening for the key regulators of cancer metastasis, we observed that neurotrophin receptor TrkB is frequently overexpressed in breast cancer patients and breast cancer cell lines. Additionally, we demonstrate that TrkB expression and clinical breast tumor pathological phenotypes show significant correlation. Moreover, TrkB expression was significantly upregulated in basal-like, claudin-low, and metaplastic breast cancers from a published microarray database and in patients with triple-negative breast cancer, which is associated with a higher risk of invasive recurrence. Interestingly, we identified a new TrkB-regulated functional network that is important for the tumorigenicity and metastasis of breast cancer. We demonstrated that TrkB plays a key role in regulation of the tumor suppressors Runx3 and Keap1. A markedly increased expression of Runx3 and Keap1 was observed upon knockdown of TrkB, treatment with a TrkB inhibitor, and in TrkB kinase dead mutants. Additionally, the inhibition of PI3K/AKT activation significantly induced Runx3 and Keap1 expression. Furthermore, we showed that TrkB enhances metastatic potential and induces proliferation. These observations suggest that TrkB plays a key role in tumorigenicity and metastasis of breast cancer cells through suppression of Runx3 or Keap1 and that it is a promising target for future intervention strategies for preventing tumor metastasis and cancer chemoprevention.

• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.360-367
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• 2022

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

• Korean Journal of Veterinary Research
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• v.43 no.3
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• pp.317-322
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• 2003

TrkA is an essential component of the high affinity NGF receptor necessary to the mediate biological effects of the neurotrophins NGF. Here we report on the expression of TrkA in the olfactory bulb and basal nucleus of Mongolian gerbil brain during the postnatal development. The expressions of TrkA were identified in a immunohistochemical method. Higher levels of TrkA immunoreactivity were detected in septum than that in olfactory bulb and caudate putamen (CPu). But TrkA was not observed before postnatal days (PND6) in olfactory bulb and PND9 in CPu. No TrkA-positive cell was detectable in the olfactory fiber layer. Several regions, such as olfactory bulb and CPu, showed weak labeling. These data show that expression of TrkA is developmentally regulated during postnatal Mongolian gerbil brain development and suggest that high affinity neurotrophinreceptors mediate a transient response to neurotrophins in many regions during the brain ontogeny.

• BMB Reports
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• v.43 no.7
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• pp.485-490
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• 2010

Neurotrophins regulate many aspects of neuronal function through activation of the high affinity Trk receptors. Shc family proteins are implicated in the coupling of RTK to the Ras/mitogen-activated protein kinase signaling cascade. Here we report that the fourth Shc family member, ShcD, associates with TrkB receptor and regulates BDNF-induced MAPK activation. Yeast two-hybrid assay and Co-IP experiments demonstrate ShcD interacts with TrkB in a kinase-activity-dependent manner. Confocal analysis shows ShcD cololizes well with TrkB in transfected 293T cells. Subsequent mapping experiments and mutational analysis indicate that both PTB and SH2 domains are capable of binding to TrkB and PTB domain binds to TrkB NPQY motif. Furthermore, ShcD is involved in BDNF-induced MAPK activation. In summary, we demonstrate that ShcD is a substrate of TrkB and mediates TrkB downstream signaling pathway.

• Journal of Life Science
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• v.19 no.3
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• pp.403-410
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• 2009

This study investigated the effects of treadmill exercise on memory ability, cell proliferation, BDNF, and TrkB in the hippocampus and forebrain cholinergic cells in adolescent rats. Male Sprague-Dawley rats (4 weeks old) were randomly assigned to the following two groups: the sedentary group (n=10) and the exercise group (n=10). Rats in the exercise group were forced to run on a treadmill for 30 min, five times per week for 4 weeks. The latency of the step-through avoidance task was used in order to evaluate memory ability. Hippocampal brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) expression were assessed by Western blotting. Hippocampal cell proliferation and forebrain cholinergic cells were assessed by immunohistochemistry. The present study showed that treadmill running during the adolescent period significantly improved memory capability, increased hippocampal cell proliferation, up-regulated hippocampal BDNF and TrkB expression, and enhanced the number of forebrain cholinergic cells. These results suggest that regular exercise during the adolescent period may enhance memory function.

• Bulletin of the Korean Chemical Society
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• v.32 no.spc8
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• pp.2893-2894
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• 2011

• Journal of Acupuncture Research
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• v.19 no.6
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• pp.97-110
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• 2002

목적 : 본 연구는 (a) 저빈도 전침의 만성 단발성 관절염에 대한 치료 효과와 (b) 척수에서 동통과 관련되는 지표인 P 물질과 trk A mRNA의 발현조절에 미치는 영향을 연구하기 위해 실행되었다. 방법 : Complete Freund's adjuvant를 실험동물의 우측 경족근관절에 주입하여 관절염을 유발시키고 9주 동안 관찰하였다. 만성 관절염의 최적의 치료조건을 찾기 위하여 각각 세 종류의 경혈(환도, 용천, 족삼리)과 전침자극강도(0.5, 1, 2 mA)를 사용하여, 행동학적 지표로서 동통을 측정하였다. 측정 결과 가장 큰 효과를 나타낸 군을 선택하여 RT-PCR 방법을 사용하여 P 물질 및 trk A mRNA의 변화를 척수 후각과 후근신경절에서 측정하였다. 결과 : 관절의 굴신을 통한 통증 검사와 족과관절 둘레 길이 측정을 통하여 관찰한 결과 원위부에 위치한 환도에 저강도의 자극을 시행한 경우(환도, 0.5 mA)가 가장 우수한 치료 효과를 나타내었다. RT-PCR을 시행한 결과, 환측 후근신경절의 P물질이 관절염 유발 대조군의 경우 정상군에 비해 증가하였고 환도-0.5mA 군에서 다시 감소하는 것을 관찰하였으며, trk A는 관절염 유발군의 경우 척수 후각에서 양측성 증가를 나타내었고 이는 전침치료에 의해 다시 감소되는 것을 관찰하였다. 결론 : 환도 0.5mA의 저빈도 전침은 관절염을 효과적으로 감소시킬 뿐 아니라 관절염으로 증가된 후근신경절의 P 물질과 척수후각의 trk A mRNA 발현을 효과적으로 감소시켰으며, 이는 원위취혈로 선혈된 환도혈의 만성관절염에 대한 치료효과를 분명히 보여준다고 할 수 있다.

• International Journal of Oral Biology
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• v.39 no.2
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• pp.107-114
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• 2014

Taste is an important sense in survival and growth of animals. The growth and maintenance of taste buds, the receptor organs of taste sense, are under the regulation of various neurotrophic factors. But the distribution aspect of neurotrophic factors and their receptors in distinct taste cell types are not clearly known. The present research was designed to characterize mRNA expression pattern of neurotrophic factors and their receptors in distinct type of taste cells. In male 45-60 day-old Sprague-Dawley rats, epithelial tissues with and without circumvallate and folliate papillaes were dissected and homogenized, and mRNA expressions for neurotrophic factors and their receptors were determined by RT-PCR. The mRNA expressions of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), receptor tyrosine kinase B (TrkB), exclusion of nerve growth factor (NGF), neurotrophin-4/5 (NT4/5), receptor tyrosine kinase A (TrkA), receptor tyrosine kinase C (TrkC), and p75NGFR were observed in some population of taste cell. In support of this result and to characterize which types of taste cells express NT3, BDNF, or TrkB, we examined mRNA expressions of NT3, BDNF, or TrkB in the $PLC{\beta}2$ (a marker of Type II cell)-and/or SNAP25 (a marker of Type III cell)-positive taste cells by a single taste cell RT-PCR and found that the ratio of positively stained cell numbers were 17.4, 6.5, 84.1, 70.3, and 1.4 % for $PLC{\beta}2$, SNAP25, NT3, BDNF, and TrkB, respectively. In addition, all of $PLC{\beta}2$-and SNAP25-positive taste cells expressed NT3 mRNA, except for one taste bud cell. The ratios of NT3 mRNA expressions were 100% and 91.7% in the SNAP25-and $PLC{\beta}2$-positive taste cells, respectively. However, two TrkB-positive taste cells co-expressed neither $PLC{\beta}2$ nor SNAP 25. The results suggest that the most of type II or type III cells express BDNF and NT3 mRNA, but the expression is shown to be less in type I taste cells.