Brain-derived neurotrophic factor (BDNF) signaling

Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for growth, differentiation, plasticity, and survival of neurons. BDNF is also required for processes such as energy metabolism, behavior, mental health, learning, memory, stress, pain and apoptosis. BDNF is implicated in various neuronal disorders such as Alzheimer's disease, Huntington's disease, depression, and bipolar disorder. BDNF binds to tyrosine kinase receptor known as tropomyosin-related kinase B (TrkB). It also binds with low affinity to p75 neurotrophin receptor (p75NTR). BDNF and its receptors are expressed throughout the central and peripheral nervous system. BDNF signaling is elicited when it dimerizes and binds to TrkB, resulting in the receptor dimerization and autophosphorylation. The activation of the receptor results in its interaction with molecules such as Shp2, Shc and PLC-gamma. These molecules further interact and modify their downstream targets leading to various neuronal processes. BDNF activates the signaling cascades such as PLC/PKC, PI3K/Akt, Ras/Erk, AMPK/ACC and NFκB pathways. BDNF through PLC/PKC pathway leads to release of intracellular calcium and regulation of synaptic plasticity. It also maintains synaptic plasticity through cAMP/PKA signaling. Activation of PI3K/Akt pathway through BDNF/TrkB interaction inhibits cell apoptosis by decreasing the expression of BIM. However, BDNF/p75NTR interaction activates JNK through TRAF6, which leads to apoptosis. Activation of JNK3 also leads to proteolytic cleavage of the p75NTR by TACE. PI3K/Akt also leads to activation of mTOR pathway and subsequently protein synthesis. Ras/Erk signaling is involved in cell proliferation, differentiation and protection of neurons. BDNF also leads to neuronal survival through Erk5/Mef pathway. Phosphorylation of synapsin by Erk1/2 leads to neurotransmitter release. BDNF signaling leads to nitric oxide production through NFκB pathway. BDNF induces neurite outgrowth through activation of JAK/STAT, Rac, and Cdc42 pathways. BDNF enhances oxidation of fat through AMPK mediated inhibition of ACC. It also plays role in microtubule assembly through inhibition of GSK3-beta. It leads to oxidative neuronal necrosis through activation of NCF molecules. BDNF also regulates the surface expression of AMPA and NMDA receptors. BDNF also regulates the expression of genes leading to processes such as differentiation of dendrites and calcification of cementoblast-like cells. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2380 CPTAC Assay Portal]

脑源性神经营养因子（BDNF）是一种对神经元生长、分化、可塑性和存活至关重要的神经营养素。BDNF亦对能量代谢、行为、心理健康、学习、记忆、应激、疼痛及细胞凋亡等过程至关重要。BDNF与多种神经元疾病密切相关，如阿尔茨海默病、亨廷顿病、抑郁症及双相情感障碍等。BDNF与酪氨酸激酶受体——肌钙蛋白相关激酶B（TrkB）结合，同时以低亲和力与p75神经营养素受体（p75NTR）结合。BDNF及其受体在中央和周围神经系统广泛表达。当BDNF二聚化并与TrkB结合时，触发受体二聚化和自磷酸化，从而引发BDNF信号传导。受体的激活导致其与Shp2、Shc和PLC-γ等分子相互作用。这些分子进一步相互作用并修饰其下游靶标，导致各种神经元过程。BDNF激活的信号级联包括PLC/PKC、PI3K/Akt、Ras/Erk、AMPK/ACC和NFκB途径。BDNF通过PLC/PKC途径导致细胞内钙离子的释放和突触可塑性的调节。它还通过cAMP/PKA信号传导维持突触可塑性。BDNF/TrkB相互作用通过降低BIM的表达，抑制PI3K/Akt途径的激活，从而抑制细胞凋亡。然而，BDNF/p75NTR相互作用通过TRAF6激活JNK，导致细胞凋亡。JNK3的激活也导致TACE介导的p75NTR蛋白水解裂解。PI3K/Akt还导致mTOR途径的激活，进而促进蛋白质合成。Ras/Erk信号传导参与细胞增殖、分化和神经元保护。BDNF还通过Erk5/Mef途径导致神经元存活。Erk1/2的磷酸化导致突触素释放。BDNF通过NFκB途径导致一氧化氮的产生。BDNF通过激活JAK/STAT、Rac和Cdc42途径诱导轴突生长。BDNF通过AMPK介导的ACC抑制增强脂肪的氧化。它还通过抑制GSK3-β在微管组装中发挥作用。它通过激活NCF分子导致氧化性神经元坏死。BDNF还调节AMPA和NMDA受体的表面表达。BDNF还调节导致树突分化、成骨细胞样细胞钙化的基因表达。该途径上的蛋白质可通过[https://assays.cancer.gov/available_assays?wp_id=WP2380 CPTAC检测门户]进行靶向检测。