Role of CDK5 in neuronal development
Cyclin-dependent kinase 5 (CDK5) is a member of the small
serine/threonine cyclin-dependent kinase (CDK) family.
One of the important roles of CDK5 is a neuronal development and
differentiation. There are several activators of CDK5. Role of
Neuronspecific activator, cyclin-dependent kinase 5 regulatory subunit 1
(CDK5R1(p35)) in neuron development and differentiation is most
CDK5R1(p35)/ CDK5 controls axonal transport of organelles and
proteins (both axonal and anterograde).
One of the most well-known pathways is the CDK5 regulation of Reelin
signaling. Reelin is a large secreted signaling glycoprotein that
binds to two members of the Low-density lipoprotein receptor family, the
Apolipoprotein E receptor-2 (ApoER2) and the Very-low-density
lipoprotein receptor (VLDLR). Reelin-activated ApoER2
and VLDLR activate Disabled-1 (Dab1) .
It is believed that Dab1 induces protein-tyrosine kinase Fyn
activation and is phosphorylated in return .
Then, Fyn-phosphorylated Dab1 activatesPhosphoinositide-3-kinase
(PI3K)/ v-akt murine thymoma viral oncogene homolog 1 (AKT)/
Glycogen synthase kinase 3 beta (GSK3 beta) pathway .
It is known that GSK3 beta is implicated in the regulation of
anterograde axonal transport, possibly via phosphorylation of
Microtubule-associated protein tau (Tau (MAPT)) .
CDK5R1(p35)/ CDK5 inhibited this pathway via phosphorylation of Dab1
In addition, it is shown that CDK5R1(p35)/ CDK5 phosphorylates
Thiol-activated peptidase (NUDEL). NUDEL, along withPlatelet-activating
factor acetylhydrolase, isoform Ib alpha subunit (PAFAH1B1(LIS1)),
interacts with Dynein 1, cytoplasmic, heavy chain, and thus
regulates axonal retrograde transport , .
Moreover, it is known that CDK5R1(p35)/ CDK5 may regulate
neurofilament transport via phosphorylation of Neurofilament H (NEFH),
Neurofilament M (NEFM) and Neurofilament L (NEFL) ,
 that all are bound to Dynein/ Dynactin
motor complex , .
It is shown that phosphorylation of the neurofilaments by CDK5R1(p35)/
CDK5 can also regulate neurite outgrowth and axon radial growth ,
CDK5R1(p35)/ CDK5 regulates formation of dendrites during
neuronal development. CDK5R1(p35)/ CDK5 directly phosphorylates Beta-catenin
and Delta-catenin at Ser-246. Phosphorylated catenins may
interact with Protein NIMA-interacting 1 (Pin1) that inhibits
catenin degradation . It leads to
stimulation of dendrites formation.
On the other hand, CDK5R1(p35)/ CDK5 phosphorylates the
Wiskott-Aldrich syndrome protein (WASP)-family veroroline homologous
protein 1 (WASF1(WAVE1)). Phosphorylation of WASF1(WAVE1)
inhibits its ability to regulate Arp2/3 complex-dependent Actin
polymerization and decrease the number of spines on the mature dendrites
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