Extraneuronal roles of cyclin‐dependent kinase 5

Rosales, Jesusa L.; Lee, Ki-Young

doi:10.1002/bies.20473

Cited by 106 publications

(100 citation statements)

References 95 publications

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“…This implies that CDK5-p35 activity is required for optimum levels of GTP-induced secretion from primary (azurophil) and secondary (specific) granules [37,38]. We found no change in levels of CD11b localization (which resides in secondary granules) upon treatment with R-roscovitine when compared with control.…”

Section: Discussionmentioning

confidence: 59%

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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Successful resolution of inflammation requires inflammatory cells such as neutrophils to undergo apoptosis prior to non-inflammatory phagocytosis by professional phagocytes. Recently, cyclin-dependent kinase (CDK) inhibitors (e.g. R-roscovitine) have been shown to induce neutrophil apoptosis and enhance the resolution of inflammation. Interestingly, NF-jB and MAPK pathways and key endogenous survival proteins (typified by Mcl-1) are involved in the regulation of neutrophil apoptosis and, in cancer-cell lines, have been implicated as possible targets of CDK inhibitors. Here, we demonstrate that R-roscovitine over-rides TNF-a and LPS-induced survival (determined by morphological examination and binding of fluorescently labelled annexin-V) of isolated peripheral blood neutrophils. This effect did not appear to be mediated via effects on early markers of neutrophil activation (e.g. surface marker expression, shape change, aggregation and superoxide anion generation), by direct inhibition of NF-jB activation (assessed by cytoplasmic IjBa proteolysis and NF-jB p65 subunit translocation) and ERK activation (determined by specific ERK phosphorylation) but due to down-regulation (at protein and mRNA level) of the survival protein Mcl-1 but not the pro-apoptotic bcl-2 homologue Bim. These findings suggest that key endogenous survival proteins may be the targets of CDK inhibitors and consequently may be of critical importance in the resolution of inflammation.

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Section: Discussionmentioning

confidence: 59%

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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“…Initially, CDK5 was implied in the regulation of neuronal functions including cytoskeletal remodeling and synaptic transmissions. Recently, an increasing array of evidence established its function and presence in nonneuronal cells as well (24). CDK5 has been shown as a regulator of the association between GLUT4 and the synaptotagmin homolog, E-syt1, to modulate glucose transport in adipocytes upon insulin stimulation (25).…”

Section: Discussionmentioning

confidence: 99%

Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy

Nair

Hocher

Verkaart

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

137

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Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 (V 1393 I, K 1584 E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 (V 1393 I) and TRPM6(K 1584 E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T 1391 ) and TRPM6(S 1583 ). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V 1393 I) and TRPM6(K 1584 E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V 1393 I) and TRPM6(K 1584 E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6. G estational diabetes mellitus (GDM) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. Babies born to mothers with GDM are typically at increased risk of large for gestational age (LGA), low blood sugar, and jaundice (1). Women with GDM are at a higher risk for preeclampsia and Caesarean section (1) as well as developing diabetes mellitus type 2 (DM2) later in life (2). GDM affects 3-10% of pregnancies, depending on the population studied. No specific cause has been identified, but it is believed that in particular sex hormones (i.e., estrogen, progesterone, prolactin) produced during pregnancy increases a woman's resistance to insulin, resulting in impaired glucose tolerance (1, 3). Moreover, pregnant women are prone to lose magnesium (Mg 2+ ). Bardicef et al. (4) demonstrated that pregnancy itself is a condition of intracellular Mg 2+ depletion. This depletion was more pronounced in women affected by GDM. The elevation in female hormones as well as Mg 2+ deficiency during pregnancy impairs insulin sensitivity and these disturbances may even act synergistically.There is growing evidence suggesting that Mg 2+ deficiency is a significant risk factor for the development of insulin resistance and subsequently hypertension and DM2 (5-8), but the underlying molecular mechanism is unknown. The first evidence suggesting a direct connection between Mg 2+ deficiency and the occurrence of metabolic diseases came from the identification of a monogenic disease primarily characterized by significant hypomagnesemia that was caused by a mutation in a mitochondrial tRNA (9). Moreover, in a recent genome-wide association (GWA) study, it was demonstrated that certain SNPs nominally associated with hypomagnesemia also correlate with fasting glucose levels, again supporting the hypothesis of a direct link between Mg 2+ a...

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“…3B). Separate phosphorylation studies of the GSTfusions C2 (1)(2) , C2 (3) , and C2 (4)(5) revealed that only the C2 (1.2) construct was phosphorylated (Fig. 3C).…”

Section: E-syt1 Expression Is Induced During Adipocyte Differentiatiomentioning

confidence: 98%

“…In noncycling cells, Cdk5 phosphorylates multiple substrates to control such diverse phenomena as cell signaling, adhesion and motility, cytoskeletal organization, protein trafficking, and membrane fusion and dynamic organization (2). The membrane-bound Cdk5 effectors, p35/p39, direct and activate the kinase to specific membrane targets via mechanisms that are not yet well understood (3)(4)(5)(6).…”

mentioning

confidence: 99%

The atypical kinase Cdk5 is activated by insulin, regulates the association between GLUT4 and E-Syt1, and modulates glucose transport in 3T3-L1 adipocytes

Lalioti

Muruáis

Dinarina

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Here, we report that Cdk5 activation is stimulated by insulin and plays a key role in the regulation of GLUT4-mediated glucose uptake in 3T3-L1 adipocytes. Insulin activation of Cdk5 requires PI3K signaling. Insulin-activated Cdk5 phosphorylates E-Syt1, a 5 C2-domain protein-related to the synaptotagmins that is induced during adipocyte differentiation. Phosphorylated E-Syt1 associates with GLUT4, an event inhibited by the Cdks inhibitor roscovitine. Cdk5 silencing inhibits glucose uptake by 3T3-L1 adipocytes. These studies elucidate a previously unknown activity of Cdk5 and demonstrate the involvement of this kinase in the regulation of insulin-dependent glucose uptake in adipocytes.T he atypical Cdc2-related protein kinase Cdk5 is ubiquitously expressed in mammalian cells and tissues (1). In noncycling cells, Cdk5 phosphorylates multiple substrates to control such diverse phenomena as cell signaling, adhesion and motility, cytoskeletal organization, protein trafficking, and membrane fusion and dynamic organization (2). The membrane-bound Cdk5 effectors, p35/p39, direct and activate the kinase to specific membrane targets via mechanisms that are not yet well understood (3-6). Cdk5 plays a crucial regulatory role in glucosestimulated insulin secretion in pancreatic cells (7,8). In addition, CDK5 is involved in the loss of ␤ cell function under glucotoxic conditions, revealing the potential therapeutic value of CDK5 inhibitors in the treatment of type 2 diabetes. Recently, fine mapping and genome-wide association studies have identified SNPs that affect a p35 homolog (9, 10) and calpain 10 (11) as being associated with type 2 diabetes susceptibility. The finding that the specific and strong Cdks inhibitor roscovitine inhibited 2DOG uptake by adipocytes has led us to investigate the involvement of Cdk5 in the regulation of glucose uptake in 3T3-L1 adipocytes.Here, we report that insulin stimulates Cdk5 activity in 3T3-L1 adipocytes, and knockdown of the kinase inhibits glucose uptake in these cells. Insulin-activated Cdk5 phosphorylates the synaptotagmin homolog E-Syt1 and promotes its association with GLUT4. Both E-Syt1 phosphorylation and GLUT4 association are inhibited by roscovitine. These findings are discussed in the context of the regulation of GLUT4-mediated glucose uptake in adipocytes, Cdk5 deregulation in response to calpains, and the susceptibility of families with the calpain 10 SNP-44 polymorphism to develop type 2 diabetes. ResultsCdk5 and p35 Are Coexpressed with GLUT4. We found comparable levels of Cdk5 transcript and protein in all GLUT4-expressing tissues and cells, including skeletal muscle, cardiac tissue, epidydimal white fat, and 3T3-L1 adipocytes (Fig. 1A). Both p35 transcript and protein were also detected in all samples (Fig. 1 A). The 32-kDa Cdk5 protein was abundant and unequally distributed among cytosolic (80%) plasma membrane (9%), microsomal (5%), and nuclear (6%) fractions [supporting information (SI) Fig. S1 A]. We identified 5 species of the Cdk5 activator p35, of which the 34-35...

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Extraneuronal roles of cyclin‐dependent kinase 5

Cited by 106 publications

References 95 publications

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy

The atypical kinase Cdk5 is activated by insulin, regulates the association between GLUT4 and E-Syt1, and modulates glucose transport in 3T3-L1 adipocytes

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