Neuronal cdc2-like kinase

Lew, John I.; Wang, Jerry H.

doi:10.1016/s0968-0004(00)88948-3

Cited by 176 publications

(125 citation statements)

References 38 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…Although cdc2 and other M-phase kinases are absent in mature neurons of adult brain (Hayes et al, 1991;Meyerson et al, 1992;Okano et al, 1993), a related kinase, cdk5, is expressed abundantly in these cells (Tsai et al, 1993;Lew and Wang, 1995). To verify that the cdc2 antibodies used in the above immunocytochemical studies reacted with cdc2 and not cdk5, the specificity of the antibodies was tested by immunoblot analysis.…”

Section: Cdc2 Antibodies That Stain Ad Neurons Do Not Crossreact Withmentioning

confidence: 99%

Aberrant Expression of Mitotic Cdc2/Cyclin B1 Kinase in Degenerating Neurons of Alzheimer’s Disease Brain

et al. 1997

View full text Add to dashboard Cite

We have shown previously that M-phase phospho-epitopes accumulate in neuronal tau proteins incorporated into the hallmark neurofibrillary tangles (NFT) of Alzheimer's disease (AD). In M phase, the epitopes are produced by cdc2/cyclin B1 kinase by a highly conserved mechanism believed to be quiescent in terminally differentiated neurons of adult brain. To determine whether an M-phase mechanism is possible in AD neurons, we first investigated the presence of cdc2 and cyclin B1 in AD. Both proteins were enriched in neurons with NFT and in neurons susceptible to NFT. An antibody specific for catalytically active cdc2 stained numerous NFT-containing neurons in AD but did not react with normal neurons. Double-labeling studies showed that active cdc2 and cyclin B1 coexist in AD neurons and co-localize with AD-specific mitotic phosphoepitopes. Mitotic kinase purified from AD and normal brain, using the yeast p13suc1 protein as affinity ligand, showed higher histone H1 phosphorylation activity in AD. Accordingly, the levels of cdc2 and cyclin B1 in p13suc1 fractions from AD were higher than normal. Consistent with a physiological relationship between NFT and mitotic kinase, NFT proteins copurified with and became phosphorylated by the p13suc1-bound kinase in vitro. Furthermore, cdc2/cyclin B1 is the only one of several proline-directed kinases that created the TG/MC mitotic phospho-epitopes in recombinant tau in vitro. These findings suggest that aberrantly reexpressed cdc2/cyclin B1 in NFT-bearing neurons in AD brain contributes to the generation of M-phase phospho-epitopes in NFT. Key words: cdc2; cyclin B; p13suc1; neuronal degeneration; Alzheimer's disease; neurofibrillary tangleMarked neuronal loss in Alzheimer's disease (AD) is often preceded by deposition of neurofibrillary tangles (NFT) that contain hyperphosphorylated proteinaceous aggregates called paired helical filaments (PHF) (for review, see Terry et al., 1994) (Trojanowski et al., 1993). Although these lesions have been studied for decades, little is known about the biochemical mechanisms that produce them. We recently presented evidence that certain NFT-specific monoclonal antibodies (i.e., the TG and MC series) recognize phospho-epitopes that are of a mitotic nature, displaying a temporally restricted pattern of appearance during M phase in a variety of proliferating eukaryotic cells (Vincent et al., 1996). We also reported that the conserved M-phase MPM-2 phosphoepitope is abundant in NFT-containing neurons in AD, but is not detected in neurons of normal brain (Vincent et al., 1996). Based on these findings, we hypothesized that a mitotic posttranslational mechanism participates in the formation of NFT and the death of neurons in AD.To gather support for this hypothesis, we first isolated mitotic kinase from brain using the yeast p13suc1 protein as affinity ligand and compared the phosphorylation activity of the kinase from AD brain with that of normal brain. We found that mitotic kinase activity is elevated in AD brain in comparison with normal. We als...

show abstract

Section: Cdc2 Antibodies That Stain Ad Neurons Do Not Crossreact Withmentioning

confidence: 99%

Aberrant Expression of Mitotic Cdc2/Cyclin B1 Kinase in Degenerating Neurons of Alzheimer’s Disease Brain

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Other signaling mechanisms such as the stimulation of voltage-and ligand-activated Ca 2+ channels are important for neuronal migration by mediating arrangements of the cytoskeletal network (Komuro andRakic 1992, 1993). Dab1 could be a component of a pathway that links adhesion complexes to the actin and microtubule network by interacting with molecules such as Cdk5 that are known to regulate cytoskeletal proteins (Lew and Wang 1995;Nikolic et al 1998). Indeed, mice deficient in Cdk5 or its neuronal specific activator p35 exhibit some similarities to Reln −/− and Dab1 −/− mice (Gilmore et al 1998;Kwon and Tsai 1998).…”

Section: The Reln-signaling Pathwaymentioning

confidence: 99%

Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS

Rice¹,

Curran²

1999

Genes & Development

141

View full text Add to dashboard Cite

“…Cyclin-dependent kinase 5 (Cdk5) is a small proline-directed serine/threonine kinase that has close structural homology to other Cdks (8). Unlike other Cdks, however, the cellular functions of Cdk5 are seemingly unrelated to the cell cycle.…”

mentioning

confidence: 99%

“…Unlike other Cdks, however, the cellular functions of Cdk5 are seemingly unrelated to the cell cycle. In addition, activation of Cdk5 requires association with its noncyclin regulatory partner, p35 (or its truncated form, p25) (8,9), or its isoform, p39 (10). Cdk5 is most abundant in neurons and its activators, p35 and p39, have been presumed to be neuronspecific.…”

mentioning

confidence: 99%

GTP-dependent Secretion from Neutrophils Is Regulated by Cdk5

Rosales

Ernst

Hallows

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

We have previously shown evidence for the existence of a calcium-independent, GTP-regulated mechanism of secretion from neutrophils, but this secretory mechanism remains to be fully elucidated. Cyclin-dependent kinase 5 (Cdk5), the various substrates of which include Munc18 and synapsin 1, has been implicated in neuronal secretion. Although the Cdk5 activator, p35, and Cdk5-p35 activity are primarily associated with neurons, we report here that p35 also exists in neutrophils and that an active Cdk5-p35 complex is present in these cells. Cdk5-p35 activity in human neutrophils is mostly localized in secretory granules, which show an increase in Cdk5-p35 level and activity upon GTP stimulation. The potent Cdk5 inhibitor, roscovitine, completely blocks GTP-stimulated granule Cdk5 activity, which accompanies lactoferrin secretion from neutrophil-specific granules. Roscovitine also inhibits GTP-induced lactoferrin secretion and surface localization of the secretion markers, CD63 and CD66b, to a certain extent. Furthermore, neutrophils from wild-type mice treated with roscovitine and neutrophils from p35 ؊/؊ mice exhibit comparable surface expression levels of both CD63 and CD66b upon GTP stimulation. Although our data suggest that other molecules control GTP-induced secretion from neutrophils, it is clear that Cdk5-p35 is required to elicit the maximum GTP-induced secretory response. Our observation that multiple proteins in neutrophil granules serve as specific substrates of Cdk5 further supports the premise that the kinase is a key component of the GTPregulated secretory apparatus in neutrophils.

show abstract

Neuronal cdc2-like kinase

Cited by 176 publications

References 38 publications

Aberrant Expression of Mitotic Cdc2/Cyclin B1 Kinase in Degenerating Neurons of Alzheimer’s Disease Brain

Aberrant Expression of Mitotic Cdc2/Cyclin B1 Kinase in Degenerating Neurons of Alzheimer’s Disease Brain

Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS

GTP-dependent Secretion from Neutrophils Is Regulated by Cdk5

Contact Info

Product

Resources

About