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Literature summary for 2.7.11.22 extracted from
- Regulation and role of cyclin-dependent kinase activity in neuronal survival and death (2010), J. Neurochem., 115, 1309-1321.
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| cyclin I | - |
Homo sapiens | |
| additional information | Cdk5 Cdk5 requires the binding of p35, p25 (a C-terminal fragment of p35), or p39 as regulatory subunnits for activation, activation mechanism of Cdk5, overview | Mus musculus | |
| additional information | Cdk5 requires the binding of p35, p25 (a C-terminal fragment of p35), or p39 as regulatory subunnits for activation, activation mechanism of Cdk5, overview. Proteasomal degradation of p39 is several times slower than that of p35, and the cleavage rate is also slow for p39, implicating a smaller contribution of p39 to neurodegenerative diseases | Homo sapiens | |
| p25 | regulatory subunit | Mus musculus | |
| p25 | regulatory subunit, binding of p25 to Cdk5 forces the activation loop to adopt an extended conformation typical of active proline-directed kinases | Homo sapiens | |
| p35 | regulatory subunit, p35 is cleaved to p25 by calpain | Mus musculus | |
| p35 | regulatory subunit, p35 is cleaved to p25 by calpain | Homo sapiens | |
| p39 | regulatory subunit, an isoform of p35 with high homology but a larger C-terminal domain, and low homology in the N-terminus including a myristoylation site and a Lys-cluster in amino acids 75-85 | Homo sapiens | |
| p39 | regulatory subunit, Mice lacking p39 display an apparently normal phenotype | Mus musculus |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| expression of Cdk5 in Spodoptera frugiperda Sf9 cells | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| S159E | the mutation of Cdk5 inhibits p35 binding | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| additional information | nonionic detergent to solubilize Cdk5-p35 changes the kinase properties. Cdk1 is inhibited by Thr14/Tyr15 phosphorylation by the Wee1 family of kinases | Homo sapiens | |
| roscovitine | Cdk5-p39 is inhibited by roscovitine at concentrations nearly identical to those that inhibit Cdk5-p35 | Homo sapiens |  |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytoplasm | free Cdk5-p25 or unbound Cdk5 | Homo sapiens | 5737 | - |
| membrane | membrane association of Cdk5 via myristoylation of p35 at Gly2. When p35 is cleaved to p25 by calpain, the active Cdk5 complex is liberated from the membrane. The half-life of Cdk5 activators is increased by dissociation from membranes, and the kinase activity of Cdk5 is stimulated several fold by release from suppression after dissociation from the membrane | Homo sapiens | 16020 | - |
| additional information | Cdk5 binding from cyytoplasm to membranes, when p35 is cleaved to p25 by calpain, the active Cdk5 complex is liberated from the membrane. The half-life of Cdk5 activators is increased by dissociation from membranes, and the kinase activity of Cdk5 is stimulated several-fold by release from suppression after dissociation from the membrane. After release from membrane, a portion of the free Cdk5-p25 is translocated into the nucleus | Homo sapiens | - |
- |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + Dab1 protein | Homo sapiens | - |
ADP + Dab1 phosphoprotein | - |
? | |
| ATP + p35 protein | Homo sapiens | a nuclear transcription factor, Cdk5-p25 phosphorylates p53 on Ser15, Ser33, and Ser44 | ADP + p35 phosphoprotein | - |
? | |
| ATP + retinoblastoma protein | Homo sapiens | a tumor suppressor protein | ADP + retinoblastoma phosphoprotein | - |
? | |
| ATP + STAT3 protein | Homo sapiens | Cdk5 phosphorylates at Ser727 | ADP + STAT3 phosphoprotein | - |
? | |
| ATP + Tau protein | Homo sapiens | Cdk5-p25 has a stronger Tau-phosphorylating activity than Cdk5-p35 in neurons | ADP + Tau phosphoprotein | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
- |
- |
| Mus musculus | - |
- |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| lipoprotein | membrane association of Cdk5 via myristoylation of p35 | Mus musculus |
| lipoprotein | membrane association of Cdk5 via myristoylation of p35 | Homo sapiens |
| phosphoprotein | Cdk5 contains all three phosphorylation sites corresponding to Thr14, Tyr15, and Thr161 in Cdk1, although Thr161 in Cdk1 is changed to Ser159 in Cdk5. Cdk5 is phosphorylated at Tyr15, Cdk1 is inhibited by Thr14/Tyr15 phosphorylation by the Wee1 family of kinases. A protein kinase purified from bovine thymus as a Thr14 kinase for Cdk1 and Cdk2 phosphorylates and inhibits Cdk5. Cdk5 does not require phosphorylation at Ser159 for activation. Cdk1 requires T-loop phosphorylation at Thr161 for activation | Homo sapiens |
| phosphoprotein | Cdk5 is phosphorylated | Mus musculus |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
| recombinant Cdk5 from Spodoptera frugiperda Sf9 cells | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| brain | - |
Mus musculus | - |
| brain | - |
Homo sapiens | - |
| neuron | - |
Mus musculus | - |
| neuron | Cdk5 mainly, Cdk5 activity is predominantly detected in post-mitotic neurons | Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + Dab1 protein | - |
Homo sapiens | ADP + Dab1 phosphoprotein | - |
? | |
| ATP + Dab1 protein | Cdk5-p35 or Cdk5-p39 | Homo sapiens | ADP + Dab1 phosphoprotein | - |
? | |
| ATP + p35 protein | a nuclear transcription factor, Cdk5-p25 phosphorylates p53 on Ser15, Ser33, and Ser44 | Homo sapiens | ADP + p35 phosphoprotein | - |
? | |
| ATP + retinoblastoma protein | a tumor suppressor protein | Homo sapiens | ADP + retinoblastoma phosphoprotein | - |
? | |
| ATP + retinoblastoma protein | a tumor suppressor protein, phosphorylated by Cdk5-p25 | Homo sapiens | ADP + retinoblastoma phosphoprotein | - |
? | |
| ATP + STAT3 protein | Cdk5 phosphorylates at Ser727 | Homo sapiens | ADP + STAT3 phosphoprotein | - |
? | |
| ATP + Tau protein | Cdk5-p25 has a stronger Tau-phosphorylating activity than Cdk5-p35 in neurons | Homo sapiens | ADP + Tau phosphoprotein | - |
? | |
| ATP + Tau protein | Cdk5-p25 or Cdk5-p35 or Cdk5-p39 | Homo sapiens | ADP + Tau phosphoprotein | - |
? | |
| additional information | kinase properties of Cdk5 are similar to those of Cdk1-cyclin B. Tau and Dab1 are phosphorylated by Cdk5-p39 and Cdk5-p35 at the same sites | Homo sapiens | ? | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| Cdk1 | - |
Homo sapiens |
| Cdk5 | - |
Mus musculus |
| Cdk5 | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Mus musculus | |
| ATP | - |
Homo sapiens | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | knockout of Cdk5 by siRNA | down |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | cyclin-dependent kinase 5, Cdk5, is a member of the family of Cdks. Cdks are proline-directed Ser/Thr protein kinases that are activated by binding a regulatory subunit called cyclin, comparison of neuronal and cycling Cdks, overview. Cdk5 may have evolved from cycling Cdks to function in post-mitotic neurons | Mus musculus |
| evolution | cyclin-dependent kinase 5, Cdk5, is a member of the family of Cdks. Cdks are proline-directed Ser/Thr protein kinases that are activated by binding a regulatory subunit called cyclin, comparison of neuronal and cycling Cdks, overview. Cdk5 may have evolved from cycling Cdks to function in post-mitotic neurons | Homo sapiens |
| malfunction | Cdk5 null mice exhibit perinatal lethality with abnormal positioning of neurons in the brain. Ballooned perikarya of large neurons in the brainstem and cytoplasmic vacuoles in brain nuclei are described for Cdk5 null mice. Similar phenotypes were also observed in the p35-/- p39-/- double null mutant | Mus musculus |
| malfunction | differentiated SHSY5Y cells and human neurons show increased cell death from DNA damage induced by camptothecin treatment when Cdk5 is knocked down with siRNA. Increased sensitivity against UV-irradiation is also observed in neurons and other terminally differentiated cells such as podocytes when the expression of Cdk5 and its activators p35 or cyclin I are reduced with siRNA. Knockout of Cdk5 or p35 results in inverted layers of neurons in the cerebral cortex. Longterm inactivation of Cdk5 triggers cell death as well as hyperactivation of Cdk5 by p25. Pro-death activity is suppressed by membrane association of Cdk5 via myristoylation of p35 | Homo sapiens |
| metabolism | cycling Cdks and neuronal Cdk5 are inversely expressed during neuronal differentiation. Upon neuronal differentiation, cycling Cdks, which are active in proliferating neuronal precursor cells, are down-regulated and Cdk5-p35 is upregulated | Mus musculus |
| metabolism | cycling Cdks and neuronal Cdk5 are inversely expressed during neuronal differentiation. Upon neuronal differentiation, cycling Cdks, which are active in proliferating neuronal precursor cells, are down-regulated and Cdk5-p35 is upregulated | Homo sapiens |
| additional information | Cdk5 is a proline-directed Ser/Thr protein kinase that is activated by binding to a regulatory subunit p35 or p39, activation mechanism of Cdk5, overview | Homo sapiens |
| physiological function | Cdk5 appears to be involved in the regulation of neuronal survival both during neuronal development and under stress conditions | Mus musculus |
| physiological function | Cdk5 regulates multiple neuronal activities neuronal migration, neurite extension, and synapse formation during brain development, as well as in synaptic activities in mature neurons and neuronal cell death in neurodegenerative diseases, and it controls life and death of the neuronal cells, pro-death activities of Cdk5-p25, overview. Knockdown of Cdk5 by siRNA reduces the number of Rohon-Beard spinal sensory neurons and increases the number of apoptotic neurons in the brain. When global ischemia is induced by occlusion, Cdk5 death activity occurs in the cytoplasm but not in the nucleus, thus the pro-death activity of Cdk5 depends on the cellular localization of the active Cdk5 complex and death signaling. Cdk5 is required for phosphorylation of signal transduction and activation of transcription 3, STAT3, also related to the pathogenesis of Alzheimer's disease, Cdk5-p35 activity functions as a survival factor in a cell-death model of neurodegenerative disorders. Up-regulated Cdk5 induces phosphorylation of STAT3 at Ser727 to bind the BACE1 promoter, which enhances BACE1 transcription and leads to an increase in protein and activity of BACE1, ultimately resulting in amyloid beta production. Cdk5-p25 phosphorylates p53 on Ser15, Ser33, and Ser44, and phosphorylated p53 is prevented from Hdm-2-mediated ubiquitination and proteasomal degradation in SH-SY5Y cells | Homo sapiens |
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