Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons.
Neurotrophins are key regulators of neuronal survival and differentiation during development. Activation of their cognate receptors, Trk receptors, a family of receptor tyrosine kinases (RTKs), is pivotal for mediating the downstream functions of neurotrophins. Recent studies reveal that cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase, may modulate RTK signaling through phosphorylation of the receptor. Given the abundant expression of both Cdk5 and Trk receptors in the nervous system, and their mutual involvement in the regulation of neuronal architecture and synaptic functions, it is of interest to investigate if Cdk5 may also modulate Trk signaling. In the current study, we report the identification of TrkB as a Cdk5 substrate. Cdk5 phosphorylates TrkB at Ser478 at the intracellular juxtamembrane region of TrkB. Interestingly, attenuation of Cdk5 activity or overexpression of a TrkB mutant lacking the Cdk5 phosphorylation site essentially abolishes brain-derived neurotrophic factor (BDNF)-triggered dendritic growth in primary hippocampal neurons. In addition, we found that Cdk5 is involved in BDNF-induced activation of Rho GTPase Cdc42, which is essential for BDNF-triggered dendritic growth. Our observations therefore reveal an unanticipated role of Cdk5 in TrkB-mediated regulation of dendritic growth through modulation of BDNF-induced Cdc42 activation.
Cheung
Zelda H
ZH
Department of Biochemistry, Biotechnology Research Institute and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Chin
Wing Hong
WH
Chen
Yu
Y
Ng
Yu Pong
YP
Ip
Nancy Y
NY
D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism / Q000502:physiology*; D003712:Dendrites; D006624:Hippocampus / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D010766:Phosphorylation; D034622:RNA Interference; D020813:Receptor, trkB / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D051360:Cyclin-Dependent Kinase 5