Activated NTRK2 signals through CDK5

CDK5, in complex with its activator CDK5R1 (p35), binds to BDNF-activated NTRK2 (TRKB). NTRK2 promotes CDK5 catalytic activity by phosphorylating CDK5 at tyrosine residue Y15 (Cheung et al. 2007), although CDK5 can also be phosphorylated at Y15 independently of NTRK2 (Zhao et al. 2009). CDK5 phosphorylates serine residue S479 of NTRK2 (corresponds to S478 in mouse and rat) (Cheung et al. 2007, Zhao et al. 2009). Phosphorylation of NTRK2 at S479 is needed for BDNF-triggered dendritic growth (Cheung et al. 2007), hippocampal long-term potentiation (LTP) and spatial memory (Lai et al. 2012). These processes involve NTRK2-mediated activation of RHO GTPases RAC1 (Lai et al. 2012) and possibly CDC42 (Cheung et al. 2007). In cultured isolated neurons, phosphorylation at S479 affects localization of NTRK2 (Zhao et al. 2009), but this does not appear to be the case in vivo (Lai et al. 2012).<p>CDK5-mediated phosphorylation of NTRK2 was suggested to influence the level of AKT activity, downstream mTOR signaling and DLG4 (PSD-95) expression, but further elucidation is needed (Lai et al. 2012).<p>Signaling by TRKB and CDK5 plays a role in inflammation induced hypersensitivity to heat-triggered pain in rats (Zhang et al. 2014).

CDK5与其激活剂CDK5R1（p35）形成复合物，与BDNF激活的NTRK2（TRKB）结合。NTRK2通过在酪氨酸残基Y15（Cheung et al. 2007）处磷酸化CDK5来促进CDK5的催化活性，尽管CDK5在没有NTRK2的情况下也能独立于Y15磷酸化（Zhao et al. 2009）。CDK5磷酸化NTRK2的丝氨酸残基S479（在鼠和鼠中对应于S478）（Cheung et al. 2007, Zhao et al. 2009）。NTRK2在S479处的磷酸化对于BDNF触发的树突生长（Cheung et al. 2007）、海马体长时程增强（LTP）和空间记忆（Lai et al. 2012）是必需的。这些过程涉及NTRK2介导的RHO GTPases RAC1（Lai et al. 2012）和可能的CDC42（Cheung et al. 2007）的激活。在培养的孤立神经元中，S479处的磷酸化影响NTRK2的定位（Zhao et al. 2009），但在体内似乎并非如此（Lai et al. 2012）。CDK5介导的NTRK2磷酸化被推测会影响AKT活性、下游mTOR信号传导和DLG4（PSD-95）的表达水平，但需要进一步的阐明（Lai et al. 2012）。TRKB和CDK5的信号传导在引起大鼠对热触发疼痛的炎症性高敏感性中发挥作用（Zhang et al. 2014）。