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

In contrast to the wealth of information on cellular function of protein kinases, many of which are known to be the products of proto-oncogenes, little is known about how protein dephosphorylation is involved in growth control of normal and malignant cells. In the present study, roles of protein phosphatases in cell division cycle control were examined by molecular genetic approaches using a lower eukaryote, the fission yeast Schizosaccharomyces pombe. Nine protein phosphatase genes have been so far identified and characterized in this organism. Each of two (dis2+, sds21+, and ppa1+, ppa2+) gene products is highly similar to mammalian type 1 and 2A ser/thr phosphatases, respectively. The ppx1+ product is an intermediate of type 1 and 2A, while the ppb1+ product is similar to Ca(2+)-dependent type 2B. At least two protein tyrosine phosphatase genes (pyp1+ and pyp2+) exist. The cdc25 protein is now established to be a tyrosine phosphatase that activates cdc2 kinase. Some of these phosphatase genes are interrelated but have distinct, essential functions in cell cycle control. Missense mutations, deletions or high dosage expression of these phosphatase genes affect entry into and exit from mitosis, mitotic chromosome disjunction, cell size and cell shape. They seem to interact with the main regulators of mitosis, cdc2, cdc13/cyclin, cdc25 and weel, or with mitotic structural components, such as condensed chromosomes or the spindle apparatus. We show that the product of an essential gene, sds22+, is an important, positive factor in controlling the expression and modulating the activity of dis2 phosphatase.
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PMID:Protein phosphatases in cell division: how vital are they? 166 85

Microtubule-associated protein tau from Alzheimer brain has been shown to be phosphorylated at several ser/thr-pro and ser/thr-X sites (Hasegawa, M. et al., J. Biol. Chem. 267, 17047-17054, 1992). Several proline-dependent protein kinases (PDPKs) (MAP kinase, cdc2 kinase, glycogen synthase kinase-3, tubulin-activated protein kinase, and 40 kDa neurofilament kinase) are implicated in the phosphorylation of the ser-thr-pro sites. The identity of the kinase(s) that phosphorylate the ser/thr-X sites are unknown. To identify the latter kinase(s) we have compared the phosphorylation of bovine tau by several brain protein kinases. Stoichiometric phosphorylation of tau was achieved by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, protein kinase C and cyclic AMP-dependent protein kinase, but not with casein kinase-2 or phosphorylase kinase. Casein kinase-1 and calmodulin-dependent protein kinase II were the best tau kinases, with greater than 4 mol and 3 mol 32P incorporated, respectively, into each mol of tau. With the sequential addition of these two kinases, 32P incorporation approached 6 mol. Peptide mapping revealed that the different kinases largely phosphorylate different sites on tau. After phosphorylation by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, cyclic AMP-dependent protein kinase and casein kinase-2, the mobility of tau isoforms as detected by SDS-PAGE was decreased. Protein kinase C phosphorylation did not produce such a mobility shift. Our results suggest that one or more of the kinases studied here may participate in the hyperphosphorylation of tau in Alzheimer disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the phosphorylation of microtubule-associated protein tau by non-proline dependent protein kinases. 803 84

Tau protein from Alzheimer disease (AD) brain is hyperphosphorylated by both proline-dependent protein kinases (PDPKs) and non-PDPKs. It is presently unclear how PDPKs and non-PDPKs interact in tau hyperphosphorylation. Previously we have shown that non-PDPKs can positively modulate the activity of a PDPK (GSK-3) in tau phosphorylation (Singh et al. (1995) FEBS Lett. 358, 267-272). In this study we have investigated whether (A) non-PDPKs can also modulate the activity of the PDPK, cdk5, (B) a PDPK can modulate the activities of another PDPK, as well as non-PDPKs. We found that, like GSK-3, the activity of cdk5 is stimulated if tau were first prephosphorylated by any of several non-PDPKs (A-kinase, C-kinase, CK-1, CaM-kinase II). Prephosphorylation of tau by cdk5 stimulated both the rate and extent of a subsequent phosphorylation catalyzed by GSK-3. Under these conditions thr 231 phosphorylation was especially enhanced (9-fold). No significant stimulation of phosphorylation was observed when the order of these kinases was reversed (i.e. GSK-3 followed by cdk5). By contrast, prephosphorylation of tau by cdk5 served to inhibit subsequent phosphorylation catalyzed by C-kinase and CK-1, but not by A-kinase or CaM-kinase II. Our results suggest that in tau hyperphosphorylation in AD brain, cdk5-catalyzed phosphorylation may serve to upregulate the activity of GSK-3 and down-regulate the activities of C-kinase and CK-1.
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PMID:Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5. 905 86

M-phase Promoting Factor (MPF; the cyclin B-cdk 1 complex) is activated at M-phase onset by removal of inhibitory phosphorylation of cdk1 at thr-14 and tyr-15. At M-phase exit, MPF is destroyed by ubiquitin-dependent cyclin proteolysis. Thus, control of MPF activity via inhibitory phosphorylation is believed to be particularly crucial in regulating transition into, rather than out of, M-phase. Using the in vitro cell cycle system derived form Xenopus eggs, here we show, however, that inhibitory phosphorylation of cdk1 contributes to control MPF activity during M-phase exit. By sampling extracts at very short intervals during both meiotic and mitotic exit, we found that cyclin B1-associated cdk1 underwent transient inhibitory phosphorylation at tyr-15 and that cyclin B1-cdk1 activity fell more rapidly than the cyclin B1 content. Inhibitory phosphorylation of MPF correlated with phosphorylation changes of cdc25C, the MPF phosphatase, and physical interaction of cdk1 with wee1, the MPF kinase, during M-phase exit. MPF down-regulation required Ca(++)/calmodulin-dependent kinase II (CaMKII) and cAMP-dependent protein kinase (PKA) activities at meiosis and mitosis exit, respectively. Treatment of M-phase extracts with a mutant cyclin B1-cdk1AF complex, refractory to inhibition by phosphorylation, impaired binding of the Anaphase Promoting Complex/Cyclosome (APC/C) to its co-activator Cdc20 and altered M-phase exit. Thus, timely M-phase exit requires a tight coupling of proteolysis-dependent and proteolysis-independent mechanisms of MPF inactivation.
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PMID:Role for non-proteolytic control of M-phase-promoting factor activity at M-phase exit. 1732 11