Alternative titles; symbols
HGNC Approved Gene Symbol: CDK5
Cytogenetic location: 7q36.1 Genomic coordinates (GRCh38): 7:151,053,815-151,057,897 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.1 | ?Lissencephaly 7 with cerebellar hypoplasia | 616342 | Autosomal recessive | 3 |
CDK5, a member of the cyclin-dependent kinase family, is prominently expressed in postmitotic central nervous system (CNS) neurons (summary by Magen et al., 2015).
The p34(CDC2) protein kinase (116940) regulates important transitions in the eukaryotic cell cycle. Using RT-PCR of HeLa cell mRNA with degenerate primers corresponding to conserved regions of CDC2, Meyerson et al. (1992) identified cDNAs encoding 7 novel human protein kinases. They designated one of these proteins PSSALRE, following the accepted practice of naming cdc2-related kinases based on the amino acid sequence of the region corresponding to the conserved PSTAIRE motif of CDC2. The predicted 291-amino acid PSSALRE protein shares 57% identity with CDC2. The in vitro transcription/translation product has an apparent molecular weight of 31 kD by SDS-PAGE. Northern blot analysis detected PSSALRE expression in all human tissues and cell lines tested.
Cyclin-dependent kinase-5 is predominantly expressed in neurons where it phosphorylates both high molecular weight neurofilaments (NEFH; 162230) and microtubule-associated protein tau (157140) (Ohshima et al., 1995).
CDK5 is required for proper development of the mammalian CNS. To be activated, CDK5 must associate with its regulatory subunit, p35 (CDK5R1; 603460). Patrick et al. (1999) showed that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer disease (104300). This accumulation correlated with an increase in CDK5 kinase activity. Unlike p35, p25 was not readily degraded, and binding of p25 to CDK5 constitutively activated CDK5, changed its cellular location, and altered its substrate specificity. In vivo, the p25/CDK5 complex hyperphosphorylated tau, which reduced tau's ability to associate with microtubules. Moreover, expression of the p25/CDK5 complex in cultured primary neurons induced cytoskeletal disruption, morphologic degeneration, and apoptosis. Patrick et al. (1999) concluded that cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases.
Bibb et al. (1999) demonstrated that CDK5 can phosphorylate DARPP32 (604399) at threonine-75, converting it into an inhibitor of PKA (see 176911).
Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine reuptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioral changes. One such transcription factor is delta-FosB (164772), a protein that persists in striatum long after the end of cocaine exposure. Bibb et al. (2001) identified Cdk5 as a downstream target of delta-FosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of delta-FosB, or chronic cocaine administration, raised levels of Cdk5 mRNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioral effects of repeated cocaine administration. Bibb et al. (2001) concluded that changes in Cdk5 levels mediated by delta-FosB, and resulting alterations in signaling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.
Wang et al. (2003) showed that transient forebrain ischemia in rat caused hippocampal CA1 pyramidal neuronal cell death. Ischemia in these cells led to an increase in p25, which was associated with prolonged activation of CDK5. Activated CDK5 phosphorylated the NMDA receptor-2A subunit (NR2A; 138253) at ser1232, resulting in enhanced current activity through NMDA synaptic receptors. Inhibition of CDK5 or of the interaction between CDK5 and NR2A protected CA1 pyramidal cells from ischemic insult. Wang et al. (2003) concluded that modulation of NMDA receptors by CDK5 is the primary intracellular event underlying ischemic injury of CA1 pyramidal neurons.
In mice, Smith et al. (2003) showed that administration of MPTP, a toxin that damages the nigrostriatal dopaminergic pathway, resulted in an increase of cdk5 expression and activity. Inhibition of cdk5 attenuated the loss of dopaminergic neurons caused by MPTP. Smith et al. (2003) suggested that cdk5 may be a regulator of dopaminergic neuron degeneration in Parkinson disease (168600).
Xie et al. (2003) found that Fak (PTK2; 600758) phosphorylation by Cdk5 was important for microtubule organization, nuclear movement, and neuronal migration in cultured mouse neurons. Phosphorylated Fak was enriched along a centrosome-associated microtubule fork abutting the nucleus. Overexpression of a nonphosphorylatable Fak mutant resulted in disorganization of the microtubule fork and impaired nuclear movement in vitro and a neuronal positioning defect in vivo. Xie et al. (2003) concluded that CDK5 phosphorylation of FAK is critical for neuronal migration through regulation of a microtubule fork important for nuclear translocation.
Phosphorylation of doublecortin (DCX; 300121) is developmentally regulated in brain, and phosphorylation corresponds to expression of p35, the major activating subunit for CDK5. Tanaka et al. (2004) found that Dcx was phosphorylated on ser297 by Cdk5 during mouse brain development. Phosphorylation lowered the affinity of Dcx to microtubules in vitro, reduced its effect on polymerization, and displaced it from microtubules in cultured neurons. In addition, mutation of ser297 blocked the effect of Dcx on neuron migration in a fashion similar to inhibition of Cdk5 activity. Tanaka et al. (2004) concluded that DCX phosphorylation by CDK5 regulates its actions on migrating neurons through an effect on microtubules.
In beta cell-derived MIN6 cells and rat pancreatic islets, Wei et al. (2005) demonstrated that inhibition of CDK5 enhanced insulin secretion after stimulation by high concentrations of glucose, and p35-null mice also showed enhanced insulin secretion in response to a glucose challenge. In beta cells, CDK5 inhibition increased the Ca(2+) influx across the L-type voltage-dependent calcium channel (see CACNA1C; 114205) upon stimulation with high glucose, but had no effect without glucose stimulation. The inhibitory regulation by CDK5 on the beta cell calcium channel was attributed to the phosphorylation of loop II-III of CACNA1C at ser783, which prevented binding to SNARE proteins and subsequently resulted in decreased activity of the channel. Wei et al. (2005) concluded that CDK5 is part of a signaling cascade in the regulation of glucose-stimulated insulin secretion in pancreatic beta cells.
Kim et al. (2006) demonstrated that Wave1 (605035) is phosphorylated at multiple sites by Cdk5 both in vitro and in intact mouse neurons. Phosphorylation of Wave1 by Cdk5 inhibited its ability to regulate Arp2/3 complex (604221)-dependent actin polymerization. Loss of Wave1 function in vivo or in cultured neurons resulted in a decrease in mature dendritic spines. Expression of a dephosphorylation-mimic mutant of Wave1 reversed this loss of Wave1 function in spine morphology, but expression of a phosphorylation-mimic mutant did not. Cyclic AMP signaling reduced phosphorylation of the Cdk5 sites in Wave1 and increased spine density in a Wave1-dependent manner. Kim et al. (2006) concluded that phosphorylation/dephosphorylation of WAVE1 in neurons has an important role in the formation of the filamentous actin cytoskeleton, and thus in the regulation of dendritic spine morphology.
Using mouse 3T3-L1 adipocytes, Lalioti et al. (2009) found that insulin-activated Cdk5 phosphorylated Esyt1 (616670), which was induced during adipocyte differentiation. Phosphorylated Esyt1 associated with Glut4 (SLC2A4; 138190), an event inhibited by a CDK inhibitor. Silencing of Cdk5 inhibited glucose uptake by 3T3-L1 adipocytes. Lalioti et al. (2009) concluded that CDK5 is involved in regulation of insulin-dependent glucose uptake in adipocytes.
Choi et al. (2010) showed that obesity induced in mice by high fat feeding activates the protein kinase CDK5 in adipose tissues. This results in phosphorylation of the nuclear receptor PPARG (601487), a dominant regulator of adipogenesis and fat cell gene expression, at ser273. This modification of PPARG does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine adiponectin (605441). The phosphorylation of PPARG by CDK5 is blocked by antidiabetic PPARG ligands such as rosiglitazone and MRL24. This inhibition works both in vitro and vivo, and is completely independent of classic receptor transcriptional agonism. Similarly, inhibition of PPARG phosphorylation in obese patients by rosiglitazone was very tightly associated with the antidiabetic effects of this drug. Choi et al. (2010) concluded that all these findings strongly suggested that Cdk5-mediated phosphorylation of PPARG may be involved in the pathogenesis of insulin resistance and presented an opportunity for development of an improved generation of antidiabetic drugs through PPARG.
Choi et al. (2011) described novel synthetic compounds that have a unique mode of binding to PPARG, completely lack classic transcriptional agonism, and block the CDK5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity without causing the fluid retention and weight gain that are serious side effects of many of the PPARG drugs. Also, unlike thiazolidinediones, SR1664 does not interfere with bone formation in culture. Choi et al. (2011) concluded that new classes of antidiabetes drugs can be developed by specifically targeting the CDK5-mediated phosphorylation of PPARG.
By analyzing mouse visual cortex, Liang et al. (2015) showed that Cdk5 localized to both cytoplasm and nucleus of neurons, but neuronal activity promoted nuclear translocation of Cdk5 in response to visual stimulation. Cdk5 was critical for growth of dendritic arbors induced by neuronal depolarization, and nuclear localization of Cdk5 was required for dendrite development in hippocampal neurons. Microarray analysis revealed that Cdk5 regulated transcription during membrane depolarization in a bidirectional manner, as a transcriptional activator or as a transcriptional repressor, and that Bdnf (113505) was one of the most significantly downregulated genes in Cdk5 -/- neurons. Further analysis showed that Cdk5 regulated activity-dependent gene expression through modulation of Mecp2 (300005) transcriptional activity.
In mice, Dorand et al. (2016) demonstrated that Cdk5 allows medulloblastoma to evade immune elimination. Interferon-gamma (IFNG; 147570)-induced Pdl1 (605402) upregulation on medulloblastoma required Cdk5, and disruption of Cdk5 expression in a mouse model of medulloblastoma resulted in potent CD4+ T cell-mediated tumor rejection. Loss of Cdk5 resulted in persistent expression of the Pdl1 transcriptional repressors, the interferon regulatory factors Irf2 (147576) and Irf2bp2 (615332), which likely led to reduced Pdl1 expression on tumors.
Using a pull-down assay, Song et al. (2016) showed that VRK3 (619771) interacted with CDK5 in SH-SY5Y neuroblastoma cells. By interacting with VRK3, CDK5 phosphorylated VRK3 at ser108. Phosphorylation of VRK3 by CDK5 enhanced VHR (DUSP3; 600183) phosphatase activity by facilitating recruitment of phospho-ERK (see 601795) to VHR, thereby leading to downregulated ERK activation. H2O2 treatment of SH-SY5Y cells induced cleavage of the CDK5 activator p35 to p25 and caused translocation of CDK5, as well as p35 and p25, to the nucleus, which resulted in VRK3 phosphorylation at ser108 and suppression of ERK activation via VHR. Knockdown analysis showed that ser108 phosphorylation protected SH-SY5Y cells by decreasing H2O2-induced apoptosis caused by prolonged exposure to ERK activity. This protective effect against H2O2-induced apoptosis was confirmed in mouse cortical neurons by in vitro analysis and by in vivo analysis with Vrk3-deficient mice.
Ohshima et al. (1995) cloned the mouse cdk5 gene and determined that it contains 12 exons in a region of approximately 5 kb.
By fluorescence in situ hybridization, Demetrick et al. (1994) mapped the CDK5 gene to chromosome 7q36. Ohshima et al. (1995) assigned mouse cdk5 to the centromeric region of mouse chromosome 5 by interspecific backcross mapping.
In 4 affected members of a highly consanguineous Israeli Muslim family with lethal autosomal recessive lissencephaly-7 with cerebellar hypoplasia (LIS7; 606342), Magen et al. (2015) identified a homozygous splice site mutation in the CDK5 gene (123831.0001), resulting in premature termination and a complete loss of function.
Ohshima et al. (1996) generated Cdk5-null mice and found that they exhibited unique lesions in the central nervous system associated with perinatal mortality. The brains of Cdk5-null mice lacked cortical laminar structure and cerebellar foliation. In addition, the large neurons in the brainstem and in the spinal cord showed chromatolytic changes with accumulation of neurofilament immunoreactivity. The authors concluded that Cdk5 is an important molecule for brain development and neuronal differentiation and suggested that Cdk5 may play critical roles in neuronal cytoskeleton structure and organization.
Using immunohistochemistry and immunoblot experiments, Nguyen et al. (2001) found that Cdk5 activity and the p25/p35 (see 603460) ratio were abnormally elevated in the spinal cord of SOD1(G37R) transgenic mice (see 147450.0001), a mouse model for amyotrophic lateral sclerosis (ALS; 105400). Using different transgenic mouse lines with various SOD1(G37R) expression levels, Nguyen et al. (2001) observed a correlation between Cdk5 activity and the longevity of the transgenic mice. Double immunofluorescence microscopy confirmed that Cdk5 and p25 colocalize with perikaryal neurofilament accumulations in SOD1(G37R) mutant mice bred onto a neurofilament mutant background. Nguyen et al. (2001) hypothesized that perikaryal accumulations of neurofilament proteins in motor neurons may alleviate ALS pathogenesis in SOD1(G37R) mice by acting as a phosphorylation sink for Cdk5 activity, thereby reducing the detrimental hyperphosphorylation of tau and other neuronal substrates.
Cdk5, which is essential for the proper development of the CNS, is also implicated in numerous complex functions of the adult CNS, such as synaptic transmission, synaptic plasticity, and neuronal signaling. To elucidate the molecular roles of Cdk5 in the adult CNS, Hirasawa et al. (2004) abrogated neuronal expression of Cdk5 in perinatal mice using the Cre-loxP system. The Cdk5-loxP flanked mice were crossed with the Cre transgenic mice in which the Cre expression was driven by the Nefh promoter, resulting in generation of viable Cdk5 conditional knockout mice with the restricted deletion of the Cdk5 gene in specific neurons beginning around embryonic day 16.5. Twenty-five percent of the Cdk5 conditional knockout mice carrying the heterozygous Cre allele had neuronal migration defects confined to brain areas where neuronal migration continues through the perinatal period. The results indicated that abrogation of Cdk5 expression in mature neurons results in a viable mouse model that enables investigation of the molecular roles of Cdk5 in the adult CNS.
Fu et al. (2005) found reduced Erbb2 (164870) and Erbb3 (190151) phosphorylation and Erbb2 kinase activity in Cdk5-deficient mouse skeletal muscle. In addition, Cdk5-null mice displayed morphologic abnormalities at the pre- and postsynaptic neuromuscular junction, and intramuscular nerve projections exhibited profuse and anomalous branching patterns. Acetylcholine receptor clustering was also abnormal. These abnormalities were accompanied by elevated frequency of miniature endplate potentials in Cdk5-null diaphragm. Fu et al. (2005) concluded that CDK5 regulates the development of motor axons and neuromuscular synapses.
Pareek et al. (2006) found high expression of Cdk5 and p35 in primary afferent nociceptive C fibers in mouse dorsal root ganglia. Induction of inflammation in peripheral nerves resulted in increased levels of Cdk5, p35, and p25. P35-null mice showed delayed responses to painful thermal stimulation, whereas transgenic mice overexpressing p35 were hypersensitive to painful stimuli compared to controls. Pareek et al. (2006) concluded that Cdk/p35 plays a role in primary afferent nociceptive signaling.
Banks et al. (2015) created mice with Cdk5 ablated specifically in adipose tissues. These mice had both a paradoxical increase in PPAR-gamma (PPARG; 601487) phosphorylation at serine-273 and worsened insulin resistance. Unbiased proteomic studies showed that ERK kinases are activated in these knockout animals. Banks et al. (2015) demonstrated that ERK (see 601795) directly phosphorylates serine-273 of PPARG in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK; see 176872). Pharmacologic inhibition of MEK and ERK markedly improved insulin resistance in both obese wildtype mice and ob/ob mice (see 164160), and also completely reversed the deleterious effects of the Cdk5 ablation. Banks et al. (2015) concluded that these data showed that an ERK/CDK5 axis controls PPARG function and suggested that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
By in situ hybridization and immunohistochemical analyses, Shinmyo et al. (2017) showed that Cdk5 was expressed preferentially in cortical neurons of developing ferret brain. Cdk5 was essential for cortical folding, as cortical folding was reduced in cerebral cortex due to radial migration deficits of cortical neurons in Cdk5 -/- ferrets. Deletion of Cdk5 appeared to preferentially impair radial migration of upper-layer neurons among cortical neurons. Analysis with a Cdk5 inhibitor suggested that radial migration of layer 2-3 neurons was more critical than that of layers 4-6 neurons for cortical folding. Further analysis confirmed that cell proliferation and apoptosis were not involved in impaired cortical folding due to Cdk5 knockout.
In 4 affected members of a highly consanguineous Israeli Muslim family with lethal autosomal recessive lissencephaly-7 with cerebellar hypoplasia (LIS7; 616342), Magen et al. (2015) identified a homozygous G-to-A transition (g.2634G-A, GRCh37) in intron 8 of the CDK5 gene (IVS8+1G-A), resulting in the skipping of exon 8 and premature termination (Val162SerfsTer19). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family and was not found in 200 ethnically matched controls. Patient cells showed decreased amounts of mutant mRNA, consistent with nonsense-mediated mRNA decay, and undetectable levels of CDK5 protein, suggesting a complete loss of function. Complementation studies in yeast showed that the mutant protein was unable to rescue the growth defect of yeast with absence of the homologous Pho85 gene.
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