• Title, Summary, Keyword: TrkA

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Nerve growth factor-induced neurite outgrowth is potentiated by stabilization of TrkA receptors

  • Song, Eun-Joo;Yoo, Young-Sook
    • 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.

TrkB Promotes Breast Cancer Metastasis via Suppression of Runx3 and Keap1 Expression

  • Kim, Min Soo;Lee, Won Sung;Jin, Wook
    • 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.

The Distribution of TrkA in the Olfactory Bulb and Basal Nucleus of the Mongolian Gerbil after Birth (출생 후 몽골리안 저빌의 후각망울과 기저핵에서 TrkA의 분포)

  • Hou, Xilin;Park, Il-kwon;Lee, Kyung-youl;Park, Mi-sun;Kim, Sang-keun;Lee, Kang-yi;Lee, Geun-jwa;Kim, Moo-kang
    • 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.

ShcD interacts with TrkB via its PTB and SH2 domains and regulates BDNF-induced MAPK activation

  • You, Yuangang;Li, Weiqi;Gong, Yanhua;Yin, Bin;Qiang, Boqin;Yuan, Jiangang;Peng, Xiaozhong
    • 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.

Effects of Treadmill Exercise on Memory, Hippocampal Cell Proliferation, BDNF, TrkB, and Forebrain Cholinergic Cells in Adolescent Rats (트레드밀 운동이 청소년기 흰쥐의 기억력과 해마 신경세포생성, BDNF, TrkB, 그리고 전뇌 콜린 세포에 미치는 영향)

  • Lee, Hee-Hyuk
    • 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.

Effect of Low Frequency Electroacupuncture on the Chronic Monoarthritis and the Abundance of mRNA Encoding Substance P and Trk A mRNA levels at the Spinal Level in Rats (저빈도 전침이 만성 단발성 관절염 흰쥐의 관절염 치료효과 및 척수에서의 P 물질과 trk A mRNA 발현조절에 미치는 영향)

  • Park, Hi-joon;Lim, sabina;Lee, Hyang-sook;Xia, Ying-qiu;Wang, Yun;Han, Ji-sheng;Lee, Hye-jung
    • 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.

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Expression of Neurotrophic Factors and Their Receptors in Rat Posterior Taste Bud Cells

  • Park, Dong-Il;Chung, Ki-Myung;Cho, Young-Kyung;Kim, Kyung-Nyun
    • 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.

The Effects of Nerve Growth Factor Expression of Central Nerve System by Environmental Enrichment and Peripheral Nerve Electrical Stimulation in Brain Ischemia Model Rats (뇌졸중 유발 백서모델에서 환경강화와 말초신경전기자극이 중추신경계의 신경성장인자에 미치는 영향)

  • Kim, Sa-Youl;Kim, Eun-Jung;Kim, Gye-Yeop
    • The Journal of Korean Physical Therapy
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    • v.19 no.4
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    • pp.33-41
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    • 2007
  • Purpose: To investigate environmental enrichment and nerve stimulation follows in application times with the change of BDNF & Trk-B receptor in the motor cortex and spinal cord. Methods: Experimental groups were divided into the five groups. Group I: normal control group, Group II: experiment control group, Group III: sciatic never electrical stimulation after MCAO, Group IV: application of only environmental enrichment after MCAO, Group V: never electrical stimulation with environmental enrichment after MCAO. Histologic observation and coronal sections were processed individually in goat polyclonal antibody phosphorylated BDNF and rabbit polyclonal antibody Trk-B receptor. Results: In immunohistochemistric response of BDNF and Trk-B, group II were showed that lower response effect at postischemic 1 days, 3 days, and 7 days. Group V were showed that increase response effect at postischemic 3 days, 7 days and 14 days. Specially showed that the most response effect at postischemic 14 days. In neurobehavioral assessment, group V were significantly difference from other groups on between-subject effects. Conclusion: The above results suggest that combined environmental enrichment with peripheral nerve electrical stimulation in focal ischemic brain injury were more improved that the change of BDNF & Trk-B receptor expression than non treatment.

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Genistein attenuates isoflurane-induced neurotoxicity and improves impaired spatial learning and memory by regulating cAMP/CREB and BDNF-TrkB-PI3K/Akt signaling

  • Jiang, Tao;Wang, Xiu-qin;Ding, Chuan;Du, Xue-lian
    • The Korean Journal of Physiology and Pharmacology
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    • v.21 no.6
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    • pp.579-589
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    • 2017
  • Anesthetics are used extensively in surgeries and related procedures to prevent pain. However, there is some concern regarding neuronal degeneration and cognitive deficits arising from regular anesthetic exposure. Recent studies have indicated that brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB) are involved in learning and memory processes. Genistein, a plant-derived isoflavone, has been shown to exhibit neuroprotective effects. The present study was performed to examine the protective effect of genistein against isoflurane-induced neurotoxicity in rats. Neonatal rats were exposed to isoflurane (0.75%, 6 hours) on postnatal day 7 (P7). Separate groups of rat pups were orally administered genistein at doses of 20, 40, or 80 mg/kg body weight from P3 to P15 and then exposed to isoflurane anesthesia on P7. Neuronal apoptosis was detected by TUNEL assay and FluoroJade B staining following isoflurane exposure. Genistein significantly reduced apoptosis in the hippocampus, reduced the expression of proapoptotic factors (Bad, Bax, and cleaved caspase-3), and increased the expression of Bcl-2 and Bcl-xL. RT-PCR analysis revealed enhanced BDNF and TrkB mRNA levels. Genistein effectively upregulated cAMP levels and phosphorylation of CREB and TrkB, leading to activation of cAMP/CREB-BDNF-TrkB signaling. PI3K/Akt signaling was also significantly activated. Genistein administration improved general behavior and enhanced learning and memory in the rats. These observations suggest that genistein exerts neuroprotective effects by suppressing isoflurane-induced neuronal apoptosis and by activating cAMP/CREB-BDNF-TrkB-PI3/Akt signaling.