Signaling by NTRK2 (TRKB)

NTRK2 (TRKB) belongs to the family of neurotrophin tyrosine kinase receptors, also known as NTRKs or TRKs. Besides NTRK2, the family includes NTRK1 (TRKA) and NTRK3 (TRKC). Similar to other receptor tyrosine kinases (RTKs), NTRK2 is activated by ligand binding to its extracellular domain. Ligand binding induces receptor dimerization, followed by trans-autophosphorylation of dimerized receptors on conserved tyrosine residues in the cytoplasmic region. Phosphorylated tyrosines in the intracellular domain of the receptor serve as docking sites for adapter proteins, triggering downstream signaling cascaded. Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NTF4, also known as NT-4) are two high affinity ligands for NTRK2. Neurotrophin-3 (NTF3, also known as NT-3), a high affinity ligand for NTRK3, binds to NTRK2 with low affinity and it is not clear if it the low level of activation of NTRK2 by NTF3 plays a physiologically relevant role. Nerve growth factor (NGF), a high affinity ligand for NTRK1, does not interact with NTRK2. NTRK2 activation triggers downstream RAS, PI3K, and PLCgamma signaling cascades, thought to be involved in neuronal development in both the peripheral (PNS) and central nervous system (CNS). In addition, NTRK2 plays an important, but poorly elucidated, role in long-term potentiation (LTP) and learning (reviewed by Minichiello 2009). NTRK2 may modify neuronal excitability and synaptic transmission by directly phosphorylating voltage gated channels (Rogalski et al. 2000).<p><p>It was recently demonstrated that the protein tyrosine phosphatase PTPN12 negatively regulates NTRK2 signaling and neurite outgrowth. In the presence of PTPN12, NTRK2 phosphorylation at tyrosine Y816 decreases. It has not yet been demonstrated that PTPN12 acts directly to dephosphorylate Y816 (and possibly other phosphotyrosines) of NTRK2 (Ambjorn et al. 2013).<p><p>Binding of SH2D1A (SAP) to NTRK2 attenuates NTRK2 trans autophosphorylation and downstream signaling through an unknown mechanism (Lo et al. 2005).<p><p>Little is known about downregulation of NTRK2 (TRKB) receptor via ubiquitin dependent pathways (Sanchez Sanchez and Arevalo 2017). CBL, a ubiquitin ligase involved in degradation of many receptor tyrosine kinases, was shown to ubiquitinate and, unexpectedly, increase stability of NTRK2 (Pandya et al. 2014). NTRK2 undergoes ubiquitination by the TRAF6 E3 ubiquitin ligase complex. While ubiquitination by the TRAF6 complex negatively regulates NTRK2 induced AKT activation, the effect of TRAF6 mediated ubiquitination on NTRK2 protein levels has not been examined (Jadhav et al. 2008).<p><p>Downregulation of the TRKB receptor may depend on the activating ligand, with BDNF inducing more rapid ubiquitination and degradation compared to NTF4 (NT 4). NTRK2 undergoes both lysosome dependent and proteasome dependent degradation upon stimulation by BDNF, while stimulation by NTF4 may protect NTRK2 from the lysosome degradation route (Proenca et al. 2016).

NTRK2（TRKB）属于神经营养酪氨酸激酶受体家族，亦称NTRKs或TRKs。除NTRK2外，该家族还包括NTRK1（TRKA）和NTRK3（TRKC）。与其它受体酪氨酸激酶（RTKs）类似，NTRK2通过其细胞外结构域与配体结合而被激活。配体结合诱导受体二聚化，随后在细胞质区域的保守酪氨酸残基上发生二聚化受体的跨膜自磷酸化。受体细胞内域的磷酸化酪氨酸作为适配蛋白的停靠位点，触发下游信号级联反应。脑源性神经营养因子（BDNF）和神经营养素-4（NTF4，亦称NT-4）是NTRK2的两个高亲和力配体。神经营养素-3（NTF3，亦称NT-3），作为NTRK3的高亲和力配体，与NTRK2的结合亲和力较低，且尚不清楚NTF3诱导的NTRK2低水平激活是否具有生理学意义。神经生长因子（NGF），作为NTRK1的高亲和力配体，不与NTRK2相互作用。NTRK2的激活触发了下游的RAS、PI3K和PLCgamma信号级联反应，这些反应被认为与外周神经系统（PNS）和中枢神经系统（CNS）中的神经元发育有关。此外，NTRK2在长期增强（LTP）和学习过程中扮演着重要但尚不明确的角色（Minichiello，2009年综述）。NTRK2可能通过直接磷酸化电压门控通道（Rogalski等人，2000年）来调节神经元的兴奋性和突触传递。<p><p>最近的研究表明，蛋白酪氨酸磷酸酶PTPN12对NTRK2信号传导和轴突生长具有负调节作用。在PTPN12存在的情况下，NTRK2在酪氨酸Y816处的磷酸化程度降低。尚未证明PTPN12直接作用于去磷酸化Y816（以及可能的其他磷酸化酪氨酸）的NTRK2（Ambjorn等人，2013年）。<p><p>SH2D1A（SAP）与NTRK2的结合通过一种未知的机制减弱了NTRK2的跨膜自磷酸化和下游信号传导（Lo等人，2005年）。<p><p>关于NTRK2（TRKB）受体通过泛素依赖途径下调的了解甚少（Sanchez Sanchez和Arevalo，2017年）。CBL，一种参与许多受体酪氨酸激酶降解的泛素连接酶，已被证明可以泛素化NTRK2，并且出人意料地增加了其稳定性（Pandya等人，2014年）。NTRK2通过TRAF6 E3泛素连接酶复合物发生泛素化。虽然TRAF6复合物的泛素化负调节NTRK2诱导的AKT激活，但TRAF6介导的泛素化对NTRK2蛋白水平的影响尚未得到研究（Jadhav等人，2008年）。<p><p>TRKB受体的下调可能取决于激活配体，BDNF诱导的泛素化和降解比NTF4（NT 4）更快。NTRK2在BDNF刺激下经历溶酶体依赖性和蛋白酶体依赖性降解，而NTF4的刺激可能保护NTRK2免受溶酶体降解途径的影响（Proenca等人，2016年）。