Cdk5, the multifunctional surveyor

Lalioti, Vassiliki; Pulido, Daniel; Sandoval, Ignacio V.

doi:10.4161/cc.9.2.10466

Cited by 64 publications

(69 citation statements)

References 295 publications

(440 reference statements)

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“…9 Although Cdk5 shares homology with other cyclin-dependent kinases, it does not depend on association with cyclins for activity. Rather, Cdk5 interacts with its obligate partner proteins, p35 and p39, [10][11][12][13] whose constitutive expression in postmitotic neurons is essential for the many known functions of Cdk5 in the regulation of cytoarchitecture, synaptic function, and dopamine signaling in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Askew

Pareek

Eid

et al. 2017

Blood

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Section: Introductionmentioning

confidence: 99%

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Askew

Pareek

Eid

et al. 2017

Blood

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“…Unlike other members of the cyclindependent kinase family, Cdk5 is activated by the non-cyclin cofactor Cdk5 regulatory subunit 1 (Cdk5r1; also known as p35) (Chae et al, 1997) and is not involved in cell cycle regulation (Dhavan and Tsai, 2001;Lalioti et al, 2010). While Cdk5 has been intensively studied in the context of neural development, several studies have begun to hint at an important role outside the nervous system (Dhavan and Tsai, 2001;Na et al, 2015;Wei et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish

et al. 2017

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The intrahepatic biliary network is a highly branched threedimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish. Further, we identified a previously unappreciated downstream kinase cascade regulated by Cdk5. Pharmacological manipulations of this downstream kinase cascade produced a crowded branching defect in the intrahepatic biliary network and influenced actin dynamics in biliary epithelial cells. We generated larvae carrying a mutation in cdk5 regulatory subunit 1a (cdk5r1a), an essential activator of Cdk5. cdk5r1a mutant larvae show similar branching defects as those observed in Cdk5 inhibitortreated larvae. A small-molecule compound that interferes with the downstream kinase cascade rescued the mutant phenotype. These results provide new insights into branching morphogenesis of the intrahepatic biliary network.

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“…Two kinases that have been identified to modify the function of Munc18-1 are cyclin-dependent kinase 5 (Cdk5) and protein kinase C (PKC) (26). Cdk5 is a small serine/ threonine kinase that plays a pivotal role in many, in particular neuronal, processes by phosphorylating several different substrates (27,28). Nevertheless, emerging evidence has demonstrated that Cdk5 is also vital in non-neuronal tissues, for example during muscle development, wound healing, and in insulin secretion from pancreatic ␤-cells (29 -31).…”

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confidence: 99%

Munc18-1 and Munc18-2 Proteins Modulate β-Cell Ca2+ Sensitivity and Kinetics of Insulin Exocytosis Differently

Mandic

Skelin

Johansson

et al. 2011

Journal of Biological Chemistry

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Fast neurotransmission and slower hormone release share the same core fusion machinery consisting of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. In evoked neurotransmission, interactions between SNAREs and the Munc18-1 protein, a member of the Sec1/Munc18 (SM) protein family, are essential for exocytosis, whereas other SM proteins are dispensable. To address if the exclusivity of Munc18-1 demonstrated in neuroexocytosis also applied to fast insulin secretion, we characterized the presence and function of Munc18-1 and its closest homologue Munc18-2 in ␤-cell stimulus-secretion coupling. We show that pancreatic ␤-cells express both Munc18-1 and Munc18-2. The two Munc18 homologues exhibit different subcellular localization, and only Munc18-1 redistributes in response to glucose stimulation. However, both Munc18-1 and Munc18-2 augment glucose-stimulated hormone release. To maintain glucose homeostasis in the body, the pancreatic ␤-cell must in a controlled way produce, store, and secrete insulin in response to appropriate stimuli (1). Regulated membrane fusion resulting in insulin exocytosis in ␤-cells is managed by the same core SNARE 3 (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) fusion machinery that mediates release of chemical signals at highly specialized central neuronal synapses (2-4). Three conserved SNARE proteins, VAMP2, syntaxin 1A, and SNAP-25, connect vesicles with the plasma membrane by forming an exceptionally stable protein complex that holds the intrinsic, but slow, capability to perform lipid bilayer fusion (5). Except for the SNARE proteins, additional cooperating proteins are critical to guarantee speed and accuracy of diverse membrane fusion events occurring in excitable cells. Such a key accessory regulator in synaptic transmission is Munc18-1, a member of the Munc18 (mammalian homologue of the unc-18 gene) family (6). In addition to Munc18-1 (with two alternatively spliced variants, Munc18-1a and Munc18-1b), Munc18-2 and Munc18-3 isoforms have also been identified (7-9). Munc18-2, also named Munc18b or muSec1 (mammalian ubiquitously Sec1), is the closest homologue of Munc18-1, showing 63% amino acid sequence identity (7).The 67-kDa hydrophilic Munc18-1 protein has been shown to be necessary not only for vesicle exocytosis but also for docking of vesicles to the plasma membrane (10). Indeed, in the absence of Munc18-1 in neuronal cells, neither evoked nor spontaneous neurotransmission can operate (6). However, besides the reported positive effect of Munc18-1 in regulated exocytosis (6, 11-13), Munc18-1 has also been identified as a negative regulator of insulin secretion (14, 15). Still, Munc18-1 is primarily considered to be a neuronal protein, whereas the homologue Munc18-2 has a wider tissue expression profile. For instance, Munc18-2 is prominent in epithelial cells (16) and has been identified as a binding partner of Cab45, a Ca 2ϩ -binding protein prominent in pancreatic acini (17). Recently Cab45/ Munc18-2 was a...

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Cdk5, the multifunctional surveyor

Cited by 64 publications

References 295 publications

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish

Munc18-1 and Munc18-2 Proteins Modulate β-Cell Ca2+ Sensitivity and Kinetics of Insulin Exocytosis Differently

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