Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated upon association with its activators p35 or p39. Cdk5 activity is localized mainly to the nervous system, and is implicated in various cellular processes including neuronal migration, synaptic plasticity and neuronal survival. Neurotrophins, a family of trophic factors, has also been demonstrated to play crucial roles in the maintenance of neuronal survival throughout development. Actions of neurotrophins are mediated by a family of receptor tyrosine kinase (RTK) known as Trk receptors. Since Cdk5 has been observed to modulate the signaling of other RTK, we sought to examine if Cdk5 may also affect Trk signaling and functions in neurons. Sequence analysis of Trk receptors revealed that potential Cdk5 phospho...[ Read more ]

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated upon association with its activators p35 or p39. Cdk5 activity is localized mainly to the nervous system, and is implicated in various cellular processes including neuronal migration, synaptic plasticity and neuronal survival. Neurotrophins, a family of trophic factors, has also been demonstrated to play crucial roles in the maintenance of neuronal survival throughout development. Actions of neurotrophins are mediated by a family of receptor tyrosine kinase (RTK) known as Trk receptors. Since Cdk5 has been observed to modulate the signaling of other RTK, we sought to examine if Cdk5 may also affect Trk signaling and functions in neurons. Sequence analysis of Trk receptors revealed that potential Cdk5 phosphorylation sites are present in the juxtamembrane region of Trk receptors. Co-immunoprecipitation assays showed that while all members of the Trk family associated with Cdk5 and p35, only TrkB and TrkC were phosphorylated by Cdk5/p25 in in vitro kinase assay. In addition, Cdk5 and p35 were also found to interact with TrkB in rat brain. In accordance with the presence of Cdk5 phosphorylation sites in the juxtamembrane region of TrkB, TrkB juxtamembrane region was phosphorylated by Cdk5/p25 complex. Site-directed mutagenesis of the potential Cdk5 phosphorylation sites revealed that TrkB was phosphorylated by Cdk5/p25 complex on Ser 478. Importantly, Cdk5 was found to attenuate the BDNF-induced down-regulation of TrkB protein level in rat cortical neurons, in addition to mediating BDNF-triggered increase in the number of primary dendrites in rat hippocampal neurons. Taken together, these observations suggest that TrkB receptor is a p35 interacting protein and a Cdk5 substrate. Cdk5 mediates several TrkB/BDNF-induced cellular processes including BDNF-triggered TrkB down-regulation and BDNF-induced increase in the number of primary dendrites, suggesting that crosstalk between Cdk5 and TrkB signaling may exhibit crucial roles in neuronal development.