scholarly journals A Rho signaling network links microtubules to PKD controlled carrier transport to focal adhesions

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Stephan A Eisler ◽  
Filipa Curado ◽  
Gisela Link ◽  
Sarah Schulz ◽  
Melanie Noack ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Carrier Transport ◽  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Focal Adhesions ◽  
Signaling Network ◽  
Protein Kinase D ◽  
Golgi Membranes ◽  
Network Coordinates ◽  
And Function

Protein kinase D (PKD) is a family of serine/threonine kinases that is required for the structural integrity and function of the Golgi complex. Despite its importance in the regulation of Golgi function, the molecular mechanisms regulating PKD activity are still incompletely understood. Using the genetically encoded PKD activity reporter G-PKDrep we now uncover a Rho signaling network comprising GEF-H1, the RhoGAP DLC3, and the Rho effector PLCε that regulate the activation of PKD at trans-Golgi membranes. We further show that this molecular network coordinates the formation of TGN-derived Rab6-positive transport carriers delivering cargo for localized exocytosis at focal adhesions.

scholarly journals Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 483
Author(s):  
Xuejing Zhang ◽  
Jaclyn Connelly ◽  
Yapeng Chao ◽  
Qiming Jane Wang
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Biological Significance ◽  
Strong Support ◽  
Human Diseases ◽  
Protein Kinase D ◽  
Cell Functions ◽  
And Function

Protein kinase D (PKD) is a family of serine/threonine protein kinases operating in the signaling network of the second messenger diacylglycerol. The three family members, PKD1, PKD2, and PKD3, are activated by a variety of extracellular stimuli and transduce cell signals affecting many aspects of basic cell functions including secretion, migration, proliferation, survival, angiogenesis, and immune response. Dysregulation of PKD in expression and activity has been detected in many human diseases. Further loss- or gain-of-function studies at cellular levels and in animal models provide strong support for crucial roles of PKD in many pathological conditions, including cancer, metabolic disorders, cardiac diseases, central nervous system disorders, inflammatory diseases, and immune dysregulation. Complexity in enzymatic regulation and function is evident as PKD isoforms may act differently in different biological systems and disease models, and understanding the molecular mechanisms underlying these differences and their biological significance in vivo is essential for the development of safer and more effective PKD-targeted therapies. In this review, to provide a global understanding of PKD function, we present an overview of the PKD family in several major human diseases with more focus on cancer-associated biological processes.

W1590 Protein Kinase D Activation and Function in Wounded Monolayers of Rat Intestinal IEC-18 and IEC-6 Cells

2009 ◽  
Vol 136 (5) ◽  
pp. A-698
Author(s):  
James Sinnett-Smith ◽  
Steven H. Young ◽  
Xiaohua Jiang ◽  
Enrique Rozengurt
Keyword(s):  
Protein Kinase ◽  
Protein Kinase D ◽  
And Function

scholarly journals Golgi spectrin: identification of an erythroid beta-spectrin homolog associated with the Golgi complex.

1994 ◽  
Vol 127 (3) ◽  
pp. 707-723 ◽  
Author(s):  
K A Beck ◽  
J A Buchanan ◽  
V Malhotra ◽  
W J Nelson
Keyword(s):  
Golgi Complex ◽  
Structural Integrity ◽  
Functional Organization ◽  
Brefeldin A ◽  
Cell Types ◽  
Loss Of Function ◽  
Dynamic Relationship ◽  
Golgi Membranes ◽  
Golgi Structure ◽  
And Function

Spectrin is a major component of a membrane-associated cytoskeleton involved in the maintenance of membrane structural integrity and the generation of functionally distinct membrane protein domains. Here, we show that a homolog of erythrocyte beta-spectrin (beta I sigma*) co-localizes with markers of the Golgi complex in a variety of cell types, and that microinjected beta-spectrin codistributes with elements of the Golgi complex. Significantly, we show a dynamic relationship between beta-spectrin and the structural and functional organization of the Golgi complex. Disruption of both Golgi structure and function, either in mitotic cells or following addition of brefeldin A, is accompanied by loss of beta-spectrin from Golgi membranes and dispersal in the cytoplasm. In contrast, perturbation of Golgi structure without a loss of function, by the addition of nocodazole, results in retention of beta-spectrin with the dispersed Golgi elements. These results indicate that the association of beta-spectrin with Golgi membranes is coupled to Golgi organization and function.

Regulation of endothelial cell morphogenesis by the protein kinase D (PKD)/glycogen synthase kinase 3 (GSK3)β pathway

2012 ◽  
Vol 303 (7) ◽  
pp. C743-C756 ◽  
Author(s):  
Sejeong Shin ◽  
Laura Wolgamott ◽  
Sang-Oh Yoon
Keyword(s):  
Endothelial Cell ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Collagen I ◽  
Glycogen Synthase Kinase ◽  
Protein Kinase D ◽  
Dependent Manner ◽  
Vascular Morphogenesis ◽  
Tube Morphogenesis

Vascular morphogenesis is a key process for development, reproduction, and pathogenesis. Thus understanding the mechanisms of this process is of pathophysiological importance. Despite the fact that collagen I is the most abundant and potent promorphogenic molecule known, the molecular mechanisms by which this protein regulates endothelial cell tube morphogenesis are still unclear. Here we provide strong evidence that collagen I induces tube morphogenesis by inhibiting glycogen synthase kinase 3β (GSK3β). Further mechanistic studies revealed that GSK3β activity is regulated by protein kinase D (PKD). PKD inhibited GSK3β activity, which was required for collagen I-induced endothelial tube morphogenesis. We also found that GSK3β regulated trafficking of integrin α2β1 in a Rab11-dependent manner. Taken together, our studies highlight the important role of PKD in the regulation of collagen I-induced vascular morphogenesis and show that it is mediated by the modulation of GSK3β activity and integrin α2β1 trafficking.

Protein kinase D in the hypertrophy pathway

2012 ◽  
Vol 40 (1) ◽  
pp. 287-289 ◽  
Author(s):  
Yuan Yan Sin ◽  
George S. Baillie
Keyword(s):  
Heart Failure ◽  
Protein Kinase ◽  
Potential Role ◽  
Protein Kinase D ◽  
Intact Cells ◽  
Hypertrophic Growth ◽  
Cardiac Gene ◽  
And Function ◽  
Regulatory Properties

Chronic neurohormonal stimulation can have direct adverse effects on the structure and function of the heart. Heart failure develops and progresses as a result of the deleterious changes. It is well established that phosphorylation of class II HDAC5 (histone deacetylase 5) is an important event in the transcriptional regulation of cardiac gene reprogramming that results in the hypertrophic growth response. To date, experimentation on phosphorylation-mediated translocation of HDAC5 has focused on the regulatory properties of PKD (protein kinase D) within intact cells. With regard to the potential role of PKD in myocardium, recent observations raise the possibility that PKD-mediated myocardial regulatory mechanisms may represent promising therapeutic avenues for the treatment of heart failure. The present review summarizes the most recent and important insights into the role of PKD in hypertrophic signalling pathways.

scholarly journals Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis

2007 ◽  
Vol 292 (1) ◽  
pp. C24-C32 ◽  
Author(s):  
Elizabeth V. Wattenberg
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Mouse Skin ◽  
Tumor Promotion ◽  
Skin Tumor ◽  
Tumor Promoter ◽  
Kinase C ◽  
And Function

Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12- O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na+,K+-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.

scholarly journals Missense Mutations in Desmoplakin Plakin Repeat Domains Have Dramatic Effects on Domain Structure and Function

2022 ◽  
Vol 23 (1) ◽  
pp. 529
Author(s):  
Fiyaz Mohammed ◽  
Elena Odintsova ◽  
Martyn Chidgey
Keyword(s):  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Bacterial Cells ◽  
Missense Mutations ◽  
Tissue Integrity ◽  
Mutation Database ◽  
Increased Risk ◽  
And Function ◽  
Plakin Proteins

Plakin repeat domains (PRDs) are globular modules that mediate the interaction of plakin proteins with the intermediate filament (IF) cytoskeleton. These associations are vital for maintaining tissue integrity in cardiac muscle and epithelial tissues. PRDs are subject to mutations that give rise to cardiomyopathies such as arrhythmogenic right ventricular cardiomyopathy, characterised by ventricular arrhythmias and associated with an increased risk of sudden heart failure, and skin blistering diseases. Herein, we have examined the functional and structural effects of 12 disease-linked missense mutations, identified from the human gene mutation database, on the PRDs of the desmosomal protein desmoplakin. Five mutations (G2056R and E2193K in PRD-A, G2338R and G2375R in PRD-B and G2647D in PRD-C) rendered their respective PRD proteins either fully or partially insoluble following expression in bacterial cells. Each of the residues affected are conserved across plakin family members, inferring a crucial role in maintaining the structural integrity of the PRD. In transfected HeLa cells, the mutation G2375R adversely affected the targeting of a desmoplakin C-terminal construct containing all three PRDs to vimentin IFs. The deletion of PRD-B and PRD-C from the construct compromised its targeting to vimentin. Bioinformatic and structural modelling approaches provided multiple mechanisms by which the disease-causing mutations could potentially destabilise PRD structure and compromise cytoskeletal linkages. Overall, our data highlight potential molecular mechanisms underlying pathogenic missense mutations and could pave the way for informing novel curative interventions targeting cardiomyopathies and skin blistering disorders.

scholarly journals Author response: A Rho signaling network links microtubules to PKD controlled carrier transport to focal adhesions

2018 ◽  
Author(s):  
Stephan A Eisler ◽  
Filipa Curado ◽  
Gisela Link ◽  
Sarah Schulz ◽  
Melanie Noack ◽  
...  
Keyword(s):  
Carrier Transport ◽  
Focal Adhesions ◽  
Signaling Network ◽  
Author Response ◽  
Network Links

scholarly journals Genetic interactions between Protein Kinase D and Lobe mutants during eye development of Drosophila melanogaster

Hereditas ◽  
2019 ◽  
Vol 156 (1) ◽  
Author(s):  
Dieter Maier ◽  
Anja C. Nagel ◽  
Anette Preiss
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Genetic Interaction ◽  
Eye Development ◽  
Genetic Interactions ◽  
Protein Kinase D ◽  
Eye Field ◽  
The Many ◽  
Fly Eye ◽  
Regulation Of Growth

Abstract Background In Drosophila, the development of the fly eye involves the activity of several, interconnected pathways that first define the presumptive eye field within the eye anlagen, followed by establishment of the dorso-ventral boundary, and the regulation of growth and apoptosis. In Lobe (L) mutant flies, parts of the eye or even the complete eye are absent because the eye field has not been properly defined. Manifold genetic interactions indicate that L influences the activity of several signalling pathways, resulting in a conversion of eye tissue into epidermis, and in the induction of apoptosis. As information on the molecular nature of the L mutation is lacking, the underlying molecular mechanisms are still an enigma. Results We have identified Protein Kinase D (PKD) as a strong modifier of the L mutant phenotype. PKD belongs to the PKC/CAMK class of Ser/Thr kinases that have been involved in diverse cellular processes including stress resistance and growth. Despite the many roles of PKD, Drosophila PKD null mutants are without apparent phenotype apart from sensitivity to oxidative stress. Here we report an involvement of PKD in eye development in the sensitized genetic background of Lobe. Absence of PKD strongly enhanced the dominant eye defects of heterozygous L2 flies, and decreased their viability. Moreover, eye-specific overexpression of an activated isoform of PKD considerably ameliorated the dominant L2 phenotype. This genetic interaction was not allele specific but similarly seen with three additional, weaker L alleles (L1, L5, LG), demonstrating its specificity. Conclusions We propose that PKD-mediated phosphorylation is involved in underlying processes causing the L phenotype, i.e. in the regulation of growth, the epidermal transformation of eye tissue and apoptosis, respectively.

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