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).
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).
Signaling by TRKB and CDK5 plays a role in inflammation induced hypersensitivity to heat-triggered pain in rats (Zhang et al. 2014).