Cyclin-dependent Kinase 5 Promotes Insulin Exocytosis

Lilja, Lena; Yang, Shao Nian; Webb, Dominic-Luc; Juntti‐Berggren, Lisa; Berggren, Per Olof; Bark, Christina

doi:10.1074/jbc.m103776200

Cited by 91 publications

(83 citation statements)

References 73 publications

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“…It would seem that other molecules are involved in GTP-mediated secretion, but it also seems that participation of Cdk5-p35 is crucial to reach the maximum GTP-triggered secretory response. Our observations parallel a previous report that Cdk5-p35 acts as a positive regulator of insulin secretion from pancreatic ␤ cells (32). Roscovitine or dominant-negative Cdk5 expression inhibits calcium-independent ␤ cell secretion.…”

Section: Discussionsupporting

confidence: 80%

GTP-dependent Secretion from Neutrophils Is Regulated by Cdk5

Rosales

Ernst

Hallows

et al. 2004

Journal of Biological Chemistry

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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.

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Section: Discussionsupporting

confidence: 80%

GTP-dependent Secretion from Neutrophils Is Regulated by Cdk5

Rosales

Ernst

Hallows

et al. 2004

Journal of Biological Chemistry

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“…There is presently a substantial amount of data to indicate that CDK5 plays important roles in extraneuronal cells during the process of myogenesis, lens differentiation, spermatogenesis, insulin secretion, apoptosis of ovarian cells and hematopoietic cell differentiation. 3,[5][6][7][8][9][10][11] Furthermore, CDK5 has been suggested to play roles in the regulation of motility of prostate cancer cells, 12 control of glioblastoma cell invasion, 13 modulation of proliferation of medullary thyroid carcinoma cells 14 and apoptotic control of leukemia cells. 15 These potential roles of CDK5 activity in the carcinogenesis of each cell type seem to involve distinct target substrates.…”

Section: Introductionmentioning

confidence: 99%

Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population

et al. 2009

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Cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine kinase, which was originally known for its regulatory role in neuronal activities, has recently been suggested to play a role in extraneuronal activities. For example, a recent study detected overexpression of the CDK5 gene in non-small-cell lung cancer. Therefore, in order to explore the association of the CDK5 gene with lung cancer risk in a Korean population, the genotypes of the CDK5 promoter region were determined in 407 lung cancer patients and 402 normal participants. The result showed that the À904 G4A genotype affected susceptibility to lung cancer risk (odd ratios (OR)¼1.53, 95% confidence interval (CI)¼1.02-2.32). Furthermore, subsequent haplotype analysis of three single-nucleotide polymorphism (SNP) regions suggested that the A-G-C haplotype was associated with a higher overall risk of lung cancer (OR¼1.59, 95% CI¼1.16-2.18). These results suggest that CDK5 promoter polymorphisms contribute to the genetic susceptibility to lung cancer in the Korean population.

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“…We previously reported that Cdk5 is present in pancreatic ␤-cells where it acts as a positive regulator of insulin secretion (32). The goals of the present study were to investigate the expression, subcellular distribution and potential roles of p35 and p39 in Cdk5-mediated insulin secretion.…”

mentioning

confidence: 99%

“…Furthermore, several lines of research have suggested that some synaptic proteins, such as Munc18-1 and synapsin 1 are substrates for Cdk5 (20,30,31). Intriguingly, Cdk5 has been demonstrated to have the ability to both promote regulated exocytosis of insulin and function as a negative regulator of dopaminergic and glutamatergic transmission in the striatum (32,33). Moreover, Cdk5 was recently identified as a dephosphin kinase, essential for synaptic vesicle endocytosis, establishing Cdk5 as a key controller of membrane trafficking in nerve terminals (34 -36).…”

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confidence: 99%

Cyclin-dependent Kinase 5 Associated with p39 Promotes Munc18-1 Phosphorylation and Ca2+-dependent Exocytosis

Lilja

Johansson

Gromada

et al. 2004

Journal of Biological Chemistry

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Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine protein kinase that requires association with a regulatory protein, p35 or p39, to form an active enzyme. Munc18-1 plays an essential role in membrane fusion, and its function is regulated by phosphorylation. We report here that both p35 and p39 were expressed in insulin-secreting ␤-cells, where they exhibited individual subcellular distributions and associated with membranous organelles of different densities. Overexpression of Cdk5, p35, or p39 showed that Cdk5 and p39 augmented Ca 2؉ -induced insulin exocytosis. Suppression of p39 and Cdk5, but not of p35, by antisense oligonucleotides selectively inhibited insulin exocytosis. Transient transfection of primary ␤-cells with Munc18-1 templates mutated in potential Cdk5 or PKC phosphorylation sites, in combination with Cdk5 and the different Cdk5 activators, suggested that Cdk5/p39-promoted Ca 2؉ -dependent insulin secretion from primary ␤-cells by phosphorylating Munc18-1 at a biochemical step immediately prior to vesicle fusion.Exocytosis of insulin from pancreatic ␤-cells has been suggested to be mediated by the same core fusion machinery that controls all membrane fusion events in organisms ranging from yeast to human (1-3). The soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) 1 proteins are essential components of this machinery. Proteins localized in the membrane of the transported vesicle (v-SNAREs) specifically interact with proteins in the target membrane (t-SNAREs). In neurotransmitter release from synaptic vesicles, the plasma membrane-associated proteins syntaxin and synaptosomal-associated protein of 25 kDa (SNAP-25) interact with the vesicular component synaptobrevin/vesicular-associated membrane protein (VAMP) (reviewed in Refs. 4 -6). Several synaptic proteins regulating neuronal exocytosis including syntaxin, SNAP-25, VAMP, and Munc18-1 have also been identified in pancreatic ␤-cells, supporting the idea that the molecular machinery regulating insulin secretion is similar to that of neurotransmitter release from synaptic vesicles (7-11).There are a series of discrete biochemical steps leading to trans-SNARE complex formation and vesicular fusion. The vesicles need to be transported and targeted to the cell surface where they are docked, primed, and finally fused with the plasma membrane. Munc18-1, a member of the sec1/Munc18 protein family has emerged as a critical regulator of exocytosis (12)(13)(14). Indeed, Munc18-1 is shown to be important for vesicle trafficking and essential for synaptic transmission since both synaptic transmission and spontaneous neurotransmitter release is abolished in neocortical neurons from Munc18-1-null mouse mutants (15). Albeit essential for regulated exocytosis, it has been demonstrated both in pancreatic ␤-cells and in neuronal systems, that Munc18-1 may also serve as a negative regulator of secretion (11,16,17). Munc18-1 binds to syntaxin 1 and might thus negatively regulate syntaxin 1 function if the expressi...

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Cyclin-dependent Kinase 5 Promotes Insulin Exocytosis

Cited by 91 publications

References 73 publications

GTP-dependent Secretion from Neutrophils Is Regulated by Cdk5

GTP-dependent Secretion from Neutrophils Is Regulated by Cdk5

Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population

Cyclin-dependent Kinase 5 Associated with p39 Promotes Munc18-1 Phosphorylation and Ca2+-dependent Exocytosis

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