Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cyclin D1 has been associated with a wide variety of proliferative diseases but its biochemical role is unknown. In diploid fibroblasts we find that cyclin D1 is complexed with many other cellular proteins. Among them are protein kinase catalytic subunits CDK2, CDK4 (previously called PSK-J3), and CDK5 (also called PSSALRE). In addition, polypeptides of 21 kd and 36 kd are identified in association with cyclin D1. We show that the 36 kd protein is the proliferating cell nuclear antigen, PCNA. Cyclin D3 also associates with multiple protein kinases, p21 and PCNA. It is proposed that there exists a quaternary complex of D cyclin, CDK, PCNA, and p21 and that many combinatorial variations (cyclin D1, D3, CDK2, 4, and 5) may assemble in vivo. These findings link a human putative G1 cyclin that is associated with oncogenesis with a well-characterized DNA replication and repair factor.
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PMID:D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. 135 58

Neurofilament proteins and the neuron-specific microtubule-associated protein tau are phosphorylated in vivo at sites conforming to the phosphorylation consensus motif of the cell-cycle-control protein kinase, p34cdc2-cyclin. Abnormalities in the phosphorylation of these proteins are associated with neurodegenerative disorders, such as amylotrophic lateral sclerosis and Alzheimer's disease. A cdc2-like kinase composed of cyclin-dependent kinase 5 (cdk5) and a brain-specific regulatory subunit is proposed to be responsible for the cdc2-like phosphorylation of these neuronal proteins.
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PMID:Neuronal cdc2-like kinase. 787 42

Tau protein kinase II (TPKII) was reported previously to be composed of a neuron-rich cdc2-related kinase (PSSALRE/cdk5) and 23 kDa subunit. Here we show that the 23 kDa subunit is a putative activator for the kinase activity. Amino acid sequence analysis revealed that the protein was novel and included a partial similarity of amino acids to a cyclin box important for the interaction with cdc2-related kinase. These results suggest that the 23 kDa subunit, but not cyclin, activates cdk5 in neuronal cells, which no longer exhibit cell cycling but are terminally differentiated cells.
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PMID:Identification of the 23 kDa subunit of tau protein kinase II as a putative activator of cdk5 in bovine brain. 814 78

We previously reported that tau protein kinase II (TPKII) from bovine brain was composed of 30 kDa and 23 kDa subunits. The 30 kDa subunit of TPKII can be regarded as a catalytic subunit because of its ATP-binding activity. Antibodies directed against TPKII-phosphorylated tau also reacted with tau phosphorylated by cdc2 kinase obtained from starfish oocytes, indicating that TPKII and cdc2 kinase phosphorylate the same sites. We determined the amino acid sequence of the 30 kDa subunit and found it to be homologous with a cdc2-related kinase, PSSALRE/cdk5. Moreover, an antibody against PSSALRE/cdk5 reacted with the 30 kDa subunit. These results indicate that the 30 kDa subunit of TPKII is bovine homologue of PSSALRE/cdk5. Expression of the 30 kDa subunit mRNA was enhanced in juvenile rat brain. This result supports our previous hypothesis that the kinase works actively in juvenile brain.
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PMID:A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. 825 90

The adult mammalian cortex is characterized by a distinct laminar structure generated through a well-defined pattern of neuronal migration. Successively generated neurons are layered in an "inside-out" manner to produce six cortical laminae. We demonstrate here that p35, the neuronal-specific activator of cyclin-dependent kinase 5, plays a key role in proper neuronal migration. Mice lacking p35, and thus p35/cdk5 kinase activity, display severe cortical lamination defects and suffer from sporadic adult lethality and seizures. Histological examination reveals that the mutant mice lack the characteristic laminated structure of the cortex. Neuronal birth-dating experiments indicate a reversed packing order of cortical neurons such that earlier born neurons reside in superficial layers and later generated neurons occupy deep layers. The phenotype of p35 mutant mice thus demonstrates that the formation of cortical laminar structure depends on the action of the p35/cdk5 kinase.
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PMID:Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. 901 Feb 3

The protein p35 is a regulatory subunit of cyclin-dependent kinase 5. It has no recognized homology to cyclins but binds to and activates cyclin-dependent kinase 5 directly in the absence of other protein molecules. Cyclin-dependent kinase 5 was initially isolated by homology to the key cell cycle regulator cdc2 kinase and later identified as a neuronal kinase that phosphorylates histone H1, tau or neurofilaments. This kinase is localized in axons of the developing and mature nervous system. To understand the role of p35 as a regulator of cyclin-dependent kinase 5 activity in the CNS, we examined the pattern of expression of p35 mRNA in the nervous system of embryonic, early postnatal and adult mice. In separate experiments, we also examined the spatial distribution of cyclin-dependent kinase 5 mRNA and the activity of cyclin-dependent kinase 5/p35 kinase complex. Postmitotic cells express p35 mRNA immediately after they leave the zones of cell proliferation. It is also expressed in developing axonal tracts in the brain. Cyclin-dependent kinase 5 mRNA is present in postmitotic and in proliferative cells throughout the embryonic central nervous system. During early postnatal period signal for p35 mRNA declines while that for cyclin-dependent kinase 5 mRNA increases throughout the brain. In the adult brain although both p35 and cyclin-dependent kinase 5 mRNAs are expressed at relatively high levels in certain structures associated with the limbic system, considerable differences exist in the patterns of their distribution in other parts of the brain. These data suggest that the p35/cyclin-dependent kinase 5 complex may be associated with early events of neuronal development such as neuronal migration and axonal growth while in the limbic system of the mature brain it may be associated with the maintenance of neuronal plasticity.
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PMID:Temporal and spatial patterns of expression of p35, a regulatory subunit of cyclin-dependent kinase 5, in the nervous system of the mouse. 919 93

Neurofilaments (NFs), the neuron-specific intermediate (i.e. approximately 10-nm diameter) filaments are major cytoskeletal components of most neurons. In a mature mammalian neuron, NFs are co-assembled from three subunits, NF-L (low), NF-M (medium), and NF-H (high), with molecular masses of 68, 95, and 115 kDa, respectively. Neurofilament proteins (NF-Ps), particularly, NF-H, are most extensively phosphorylated in large myelinated axons under normal conditions. This phosphorylation occurs on the serine residues of the lysine (Lys)-serine (Ser)-proline (Pro) (KSP) multiple amino acid repeats of the carboxy-terminal tail domain. Phosphorylation of KSP motifs affects physical, biochemical, and immunological properties of NF-H. For example, phosphorylation is thought to play a pivotal role in the maintenance of the neuronal cytoskeletal structure which influences the conduction velocity of the nerve fiber. The key components responsible for phosphorylation are not known. In this study, an identified cyclin-dependent kinase 5 (cdk5), isolated from nervous tissue, has been shown to phosphorylate the human NF-H (hNF-H) and affects its electrophoretic mobility. On the basis of the following observations, it is suggested that neuronal cdk5 (cdk5) phosphorylates KSPXK motifs in the human high molecular weight neurofilament (hNF-H) and affects its electrophoretic mobility. (1) A 14-mer synthetic peptide (KSPEKAKSPVKEEA) derived from hNF-H; (2) a bacterially expressed protein containing 14 KSPXK multiple repeats of hNF-H in C-terminal tail domain; and (3) a dephosphorylated hNF-H in neurofilament preparation are phosphorylated by cdk5. The decrease in molecular mass of hNF-H caused by dephosphorylated was completely recovered upon cdk5 phosphorylation. It is proposed that neuronal cdk5 regulates phosphorylation of the KSPXK motif in hNF-H and other cytoskeletal proteins with similar motifs in the nervous system.
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PMID:Phosphorylation of human high molecular weight neurofilament protein (hNF-H) by neuronal cyclin-dependent kinase 5 (cdk5). 931 98

Recent work has shown that high molecular weight neurofilament (NF) proteins are phosphorylated in their carboxy-terminal tail portion by the enzyme cyclin-dependent kinase 5 (CDK-5). The tail domain of neurofilaments contains 52 tripeptide repeats, viz. Lys-Ser-Pro, which mainly exist as KSPXK and KSPXXX motifs (X = amino acid). CDK-5 specifically phosphorylates the serine residues within the KSPXK sites. We probed the structural basis for this type of substrate selectivity by studying the conformation of synthetic peptides containing either KSPXK or KSPXXX repeats designed from native neurofilament sequences. Synthetic peptides with KSPXK repeats were phosphorylated on serine with a recombinant CDK-5/p25 complex whereas those with KSPXXX repeats were unreactive in this system. Circular dichroism (CD) studies in 50% TFE/H2O revealed a predominantly helical conformation for the KSPXXX-containing peptides, whereas the CD spectra for KSPXK-containing peptides indicated the presence of a high population of extended structures in water and 50% TFE solutions. However, detailed NMR analysis of one such peptide which included two such KSPXK repeats suggested a turn-like conformation encompassing the first KSPXK repeat. Restrained molecular dynamics calculations yielded an unusually stable, folded structure with a double "S"-like bend incorporating the central residues of the peptide. The data suggest that a transient reverse turn or loop-type structure may be a requirement for CDK-5-promoted phosphate transfer to neurofilament-specific peptide segments.
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PMID:Site-specific phosphorylation of Lys-Ser-Pro repeat peptides from neurofilament H by cyclin-dependent kinase 5: structural basis for substrate recognition. 953 91

While cyclin-dependent kinase 5 (Cdk5) is widely distributed in mammalian tissues and in cultured cell lines, Cdk5-associated kinase activity has been demonstrated only in mammalian brains. An active form of Cdk5, called neuronal cdc2-like kinase (Nclk) has been purified from mammalian brain and shown to be a heterodimer of Cdk5 and a 25 kDa protein, which is derived proteolytically from a 35 kDa brain and neuron-specific protein. The protein is essential for the kinase activity of Cdk5 and is therefore designated neuronal Cdk5 activator, p25/35Nck5a. Nclk appears to have important neuronal functions. The changes in Cdk5 and Nck5a expression appear to correlate with the terminal differentiation of neurons of the mouse embryonic brain. Transfection of cultured cortical neurons with dominant negative cdk5 mutants or Nck5a antisense DNA may reduce neurite growth, suggesting that Nclk plays an active role in neuron differentiation. A number of cytoskeletal proteins including neurofilament proteins, the neuron-specific microtubule associated protein tau, and the actin binding protein caldesmon are in vitro substrates of Nclk. Although Nck5a has cyclin-like activity, it shows minimal amino acid sequence identity to members of cyclin family proteins. The mechanism of activation of Cdk5 by Nck5a differs from that of cyclin activation of Cdks in that full Cdk5 kinase activity can be achieved in the absence of phosphorylation of Cdk5. An isoform of Nck5a, a 39 kDa protein has been cloned and shown to share extensive amino acid identity and the mechanism of Cdk5 activation with Nck5a. These proteins may represent a subfamily of Cdk activators distinct from cyclins.
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PMID:Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators. 955 97

The cyclin-dependent kinase 5 (Cdk5) catalytic subunit is expressed in both cycling and noncycling cells and is present in many tissues. Neuronal and muscle cells contain the highest amount of this protein. The p35 protein, which is expressed solely in the brain, activates Cdk5. Cdk5 activity is involved in terminal differentiation of neurons and muscle cells. We attempted to clone cdk5 by PCR from a human fetal brain cDNA library. Surprisingly, we amplified two forms of the cdk5 gene, the wild type and a cdk5 variant that lacks the complete kinase domain VI. The variant is also found in SH-SY-5Y neuroblastoma cells but not in T-cells, HeLa cells, the thymus, and placental tissue. The protein encoded by the cdk5 variant, the Cdk5 isoform (Cdk5i), purifies with p35 when coexpressed in insect cells. The activity associated with the heterodimer Cdk5i/p35 is found to be appreciably weaker than the wild-type Cdk5/p35 kinase. Moreover, Cdk5i/p35 cannot autophosphorylate its two subunits as with Cdk5/p35. Interestingly, kinase-defective Cdk5i can abolish the activity of wild-type Cdk5 when both are coexpressed with p35 in insect cells, suggesting that Cdk5i may have a function in regulating Cdk5 activity in human cells too.
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PMID:Identification of a human cDNA encoding a kinase-defective cdk5 isoform. 987 33


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