Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurite outgrowth is influenced by positive and negative signals that include the semaphorins, an important family of axonal outgrowth inhibitors. Here we report that the Rac GTPase activating protein (GAP)alpha2-chimaerin is involved in Semaphorin 3A (Sema 3A) signaling. In dorsal root ganglion neurons, Sema 3A-induced growth cone collapse was inhibited by alpha2-chimaerin mutated to eliminate GAP activity or interaction with phosphotyrosine. Activation of alpha2-chimaerin by phorbol ester caused growth cone collapse. Active alpha2-chimaerin interacts with collapsin response mediator protein-2 (CRMP-2) and cyclin-dependent kinase (Cdk) 5/p35 kinase through its SH2 and GAP domains, respectively. Cdk5 phosphorylates CRMP-2 at serine 522, possibly facilitating phosphorylation of serine 518 and threonine 514 by glycogen synthase kinase 3beta (GSK3beta), a kinase previously implicated in Sema 3A signaling. Phosphorylation of CRMP-2 serine 522 was essential for Sema 3A-induced growth cone collapse, which is dependent on Cdk5 but not Rho kinase activity. alpha2-chimaerin, like CRMP-2, can associate with the Sema 3A receptor. These results indicate that active alpha2-chimaerin Rac GAP, Cdk5/p35, and its substrate CRMP-2, are implicated in the dynamics of growth cone guidance initiated through Sema 3A signaling.
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PMID:Alpha2-chimaerin, cyclin-dependent Kinase 5/p35, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. 1548 18

Cyclin-dependent kinase 5 (Cdk5), a neuronal Cdc2-like kinase, exhibits a variety of functions in neuronal differentiation and neurocytoskeleton dynamics, as well as neuronal degeneration. However, its role and induction mechanisms in retinoic acid (RA)-induced neuronal differentiation have not been well understood. In this study we newly found that RA treatment of SK-N-BE(2)C, human neuroblastoma cells, increased the expression of Cdk5 and its neuron specific activator p35 through the extracellular-signal-regulated kinase1/2 (ERK1/2) and cAMP-dependent protein kinase A (PKA) pathway. Inhibition of Cdk5 activity either by an inhibitor, roscovitine, or by transfection with a dominant negative form of Cdk5 caused a dramatic decrease in RA-induced differentiation, suggesting the requirement of Cdk5 kinase activity for the RA-induced neurite outgrowth. Furthermore, Cdk5 and p35 expression was decreased by ERK1/2 inhibition with PD98059 and increased by overexpression of a constitutive active mitogen-activated protein kinase kinase 1 (MEK1) mutant, suggesting the critical role of ERK1/2 in the induction of Cdk5 and p35. In addition, a transcription factor early growth response 1 (Egr-1) was induced by RA through the ERK1/2 pathway, suggesting its possible involvement in the p35 induction. RA treatment also induced c-fos mediated AP-1 binding, and cAMP-responsive element binding protein (CREB) mediated CRE binding via ERK1/2 and PKA pathway, respectively, in the Cdk5 promoter region, resulting in the induction of Cdk5. Our results suggest that ERK1/2 and PKA-induced regulation of Cdk5 activity possibly through Egr-1, c-fos, and CREB plays a critical role in the RA-induced neuronal differentiation.
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PMID:Induction of cyclin-dependent kinase 5 and its activator p35 through the extracellular-signal-regulated kinase and protein kinase A pathways during retinoic-acid mediated neuronal differentiation in human neuroblastoma SK-N-BE(2)C cells. 1548 94

The cyclin-dependent kinase Cdk5 and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa)-dependent signaling have been implicated in the regulation of dopaminergic neurotransmission after chronic cocaine treatment. In this study, we examined if Cdk5 signaling participates in the behavioral and biochemical effect of acute and chronic methamphetamine (METH) treatment. We found that Cdk5 activity and the membrane fraction of p35 protein, a Cdk5 activator, in the ventral striatum increased transiently after an injection of 4 mg/kg METH, while intra-accumbens treatment with a Cdk5 inhibitor, roscovitine, prevented the acute METH-induced locomotor activation. The phosphorylation of DARPP-32 at both Thr75 and Thr34 was differentially regulated after acute METH treatment, but the levels of total Cdk5, p35, and DARPP-32 remained the same. To determine if Cdk5 signaling was associated with behavior sensitization to METH, rats that received repetitive injections of METH (4 mg/kg) for 14 consecutive days were analyzed at withdrawal day 7. The results indicate that Cdk5 activity and p35 translocation in the ventral striatum were upregulated in METH-sensitized rats; treatment with roscovitine in the nucleus accumbens effectively suppressed the 1 mg/kg METH-induced behavioral sensitization. Concomitantly, a decrease in the amount of PP-2A and DARPP-32 phosphorylation at Thr34, but an increase in phosphorylation of DARPP-32/Thr75, was observed in the ventral striatum of sensitized rats. The overall results demonstrate that Cdk5/p35 and downstream signaling in the ventral striatum play a critical role in the effects of acute METH treatment as well as the development of behavioral METH sensitization.
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PMID:Enhanced Cdk5 activity and p35 translocation in the ventral striatum of acute and chronic methamphetamine-treated rats. 1553 96

Aberrant calpain activation is a key mediator of neuron death. We examined the cell-permeable calpain inhibitor MDL28170 in the pathophysiological processes after spinal cord injury (SCI) including p35-p25- cyclin-dependent kinase-5 (Cdk5) activation, tau hyperphosphorylation, neuron cell death, calpain I activation, astrogliosis, and microglia activation. Our study showed that intrathecal administration of MDL28170 improved neurologic dysfunction, prevented neuron loss, decreased the number of apoptotic cells, and abated astrogliosis and microglia activation 7 days after spinal cord hemisection in rats. Reverse transcription polymerase chain reaction demonstrated calpain inhibition significantly attenuated the ratio of proapoptotic Bax/anti-apoptotic Bcl-2 mRNA in the lesion and penumbra after SCI. Calpain, the calcium-activated proteolytic enzyme, was found to digest p35 to its truncated product, p25. Moreover, abnormal Cdk5 activation by p25 and subsequent tau hyperphosphorylation triggers pathologic events leading to neurodegeneration and neurofibrillary tangles. We found p35-p25-Cdk5 activation and tau hyperphosphorylation in SCI, and then we showed that intrathecal MDL28170 treatment could diminish p35 truncation, and abrogate aberrant tau phosphorylation. Double labeling of calpain I and phosphorylated tau (AT8) in the same cells of spinal cord lesion further implicated pathogenesis of SCI. In conclusion, MDL28170 abated calpain I activation, inhibited apoptosis and neuron loss, quenched microglia and astrocyte activation, and significantly improved neurologic deficit one week after spinal cord hemisection. The neuroprotective mechanisms of calpain inhibitor in SCI could be attenuating upregulation of Bax/Bcl-2 ratio, preventing p35 truncation in the lesion and penumbra, and abrogating tau hyperphosphorylation.
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PMID:Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats. 1571 81

The cyclin-dependent kinase inhibitors (CKIs) bind to and directly regulate the catalytic activity of cyclin-dependent kinase (Cdk)/cyclin complexes involved in cell cycle control and do not regulate other, closely related Cdks. We showed previously that the CKI, p27, binds to Cdk2/cyclin A though a sequential mechanism that involves folding-on-binding. The first step in the kinetic mechanism is interaction of a small, highly dynamic domain of p27 (domain 1) with the cyclin subunit of the Cdk2/cyclin A complex, followed by much slower binding of a more lengthy and less flexible domain (domain 2) to Cdk2. The second step requires folding of domain 2 into the kinase inhibitory conformation. Rapid binding of p27 domain 1 to cyclin A tethers the inhibitor to the binary Cdk2/cyclin A complex, which reduces the entropic barrier associated with slow binding of domain 2 to the catalytic subunit. We show here that p27/cyclin interactions are an important determinant of p27 specificity towards cell cycle Cdks. We used surface plasmon resonance, limited proteolysis, mass spectrometry, and NMR spectroscopy to study the interaction of p27 with Cdk2/cyclin A, and with another Cdk complex, Cdk5/p25, that is involved in neurodegeneration. Importantly, Cdk5/p35 (the parent complex of Cdk5/p25) is not regulated by p27 in neurons. Our results show that p27 binds to Cdk5 and Cdk2 with similar, slow kinetics. However, p27 fails to interact with p25 within the Cdk5/p25 complex, which we believe prevents formation of a kinetically trapped, inhibited p27/Cdk5/p25 complex in vivo. The helical topology of p25 is very similar to that of cyclin A. However, p25 lacks the MRAIL sequence in one helix that, in the cell cycle cyclins, mediates specific interactions with domain 1 of p21 and p27. Our results strongly suggest that p21 and p27, related Cdk inhibitors, select their cell cycle regulatory Cdk targets by binding specifically to the cyclin subunit of these Cdk/cyclin complexes as a first step in a sequential, folding-on-binding mechanism.
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PMID:Molecular basis for the specificity of p27 toward cyclin-dependent kinases that regulate cell division. 1589 Mar 60

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family that is mostly seen in neurons, does not vary with cell cycle, and is activated in many neurodegenerative disorders and other non-neuronal pathologies, but its relationship to non-neuronal apoptosis is not understood, nor is the control of the activation of Cdk5 by its activators. The most widely studied activator of Cdk5, p35, is cleaved to p25 by calpain, an event that has been linked with activation of Cdk5 and neuronal death. Here we report that calpain-mediated Cdk5/p25 activation accompanies non-neuronal as well as neuronal cell death, suggesting that the p35/calpain/p25/Cdk5 activation sequence is a general feature of cell death. We further demonstrate that Cdk5 can be activated in the absence of p53, Apaf-1, caspase-9, and -3 during cell death, indicating that its activation relates more to cell death than to a specific pathway of apoptosis.
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PMID:p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death. 1602 Nov 78

The mechanisms involving neuronal death after ischemic/hypoxic insult are complex, involving both rapid (excitotoxic) and delayed (apoptotic-like) processes. Recent evidence suggests that cell cycle regulators such as cyclin-dependent kinases are abnormally activated in neuropathological conditions, including stroke. However, the function of this activation is unclear. Here, we provide evidence that inhibition of the cell cycle regulator, Cdk4, and its activator, cyclinD1, plays critical roles in the delayed death component of ischemic/hypoxic stress by regulating the tumor suppressor retinoblastoma protein. In contrast, the excitotoxic component of ischemia/hypoxia is predominately regulated by Cdk5 and its activator p35, components of a cyclin-dependent kinase complex associated with neuronal development. Hence, our data both characterize the functional significance of the cell cycle Cdk4 and neuronal Cdk5 signals as well as define the pathways and circumstances by which they act to control ischemic/hypoxic damage.
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PMID:Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. 1616 66

Cyclin-dependent kinase 5 (cdk5) is a member of the cyclin-dependent kinase family whose activity is localized mainly to postmitotic neurons attributable to the selective expression of its activating partners p35 and p39. Deregulation of cdk5, as a result of calpain cleavage of p35 to a smaller p25 form, has been suggested to be a central component of neuronal death underlying numerous neurodegenerative diseases. However, the relevance of cdk5 in apoptotic death that relies on the mitochondrial pathway is unknown. Furthermore, evidence that cdk5 can also promote neuronal survival has necessitated a more complex understanding of cdk5 in the control of neuronal fate. Here we explore each of these issues using apoptotic and excitotoxic death models. We find that apoptotic death induced by the DNA-damaging agent camptothecin is associated with early transcription-mediated loss of p35 and with late production of p25 that is dependent on Bax, Apaf1, and caspases. In contrast, during excitotoxic death induced by glutamate, neurons rapidly produce p25 independent of the mitochondrial pathway. Analysis of the localization of p35 and p25 revealed that p35 is mainly cytoplasmic, whereas p25 accumulates selectively in the nucleus. By targeting a dominant-negative cdk5 to either the cytoplasm or nucleus, we show that cdk5 has a death-promoting activity within the nucleus and that this activity is required in excitotoxic death but not apoptotic death. Moreover, we also find that cdk5 contributes to pro-survival signaling selectively within the cytoplasm, and manipulation of this signal can modify death induced by both excitotoxicity and DNA damage.
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PMID:Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and excitotoxic neuronal death. 1619 86

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family and has been studied mainly in the differentiation of post-mitotic neurons. The purpose of this study was to determine the presence of cdk5 expression and activity in colon cancer cells and to investigate its role in the regulation of PPARgamma ligand-induced antiproliferation. We observed that cdk5 protein levels and kinase activity were elevated in both HT-29 cells and human tumor tissue in comparison to decreased levels in normal colonic mucosa. To elucidate cdk5's role in PPARgamma ligand-induced antiproliferation of colon cancer cells, HT-29 cells were treated with ciglitazone. A dose- and time-dependent decrease in cell proliferation were observed after ciglitazone exposure, which correlated with a decrease in cdk5 protein expression and kinase activity. Importantly, these ciglitazone-induced antiproliferative changes were reversed when cdk5 was overexpressed. Although present, p35, the regulatory protein of cdk5, showed no significant changes in protein expression with the introduction of ciglitazone. This is the first report of cdk5/p35 expression and kinase activity in colon cancer cells, which is associated with ciglitazone-induced antiproliferation in HT-29 cells.
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PMID:CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. 1632 95

Pctaire1, a member of the cyclin-dependent kinase (Cdk)-related family, has recently been shown to be phosphorylated and regulated by Cdk5/p35. Although Pctaire1 is expressed in both neuronal and non-neuronal cells, its precise functions remain elusive. We performed a yeast two-hybrid screen to identify proteins that interact with Pctaire1. N-Ethylmaleimide-sensitive fusion protein (NSF), a crucial factor in vesicular transport and membrane fusion, was identified as one of the Pctaire1 interacting proteins. We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569. Mutation of this phosphorylation site on NSF (S569A) augments its ability to oligomerize. Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self-association of NSF. Interestingly, Pctaire1 associates with NSF and synaptic vesicle-associated proteins in adult rat brain. To investigate whether Pctaire1 phosphorylation of NSF is involved in regulation of Ca(2+)-dependent exocytosis, we examined the effect of expressing Pctaire1 or NSF phosphorylation mutants on the regulated secretion of growth hormone from PC12 cells. Interestingly, expression of either Pctaire1-KD or NSF-S569A in PC12 cells significantly increases high K(+)-stimulated growth hormone release. Taken together, our findings provide the first demonstration that Pctaire1 phosphorylation of NSF regulates the ability of NSF to oligomerize, implicating an unexpected role of this kinase in modulating exocytosis. These findings open a new avenue of research in studying the functional roles of Pctaire1 in the nervous system.
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PMID:Pctaire1 phosphorylates N-ethylmaleimide-sensitive fusion protein: implications in the regulation of its hexamerization and exocytosis. 1646 45


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