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

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.

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

eLife ◽

10.7554/elife.35907 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 17

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.

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Regulation of Osteoclast Differentiation at Multiple Stages by Protein Kinase D Family Kinases

International Journal of Molecular Sciences ◽

10.3390/ijms21031056 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1056

Author(s):

Amanda C. Leightner ◽

Carina Mello Guimaraes Meyers ◽

Michael D. Evans ◽

Kim C. Mansky ◽

Rajaram Gopalakrishnan ◽

...

Keyword(s):

Protein Kinase ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Protein Kinase D ◽

Skeletal Health ◽

Osteoblast Activity ◽

Positive Regulators ◽

Induced Apoptosis ◽

And Function ◽

Higher Doses

Balanced osteoclast and osteoblast activity is necessary for skeletal health, whereas unbalanced osteoclast activity causes bone loss in many skeletal conditions. A better understanding of pathways that regulate osteoclast differentiation and activity is necessary for the development of new therapies to better manage bone resorption. The roles of Protein Kinase D (PKD) family of serine/threonine kinases in osteoclasts have not been well characterized. In this study we use immunofluorescence analysis to reveal that PKD2 and PKD3, the isoforms expressed in osteoclasts, are found in the nucleus and cytoplasm, the mitotic spindle and midbody, and in association with the actin belt. We show that PKD inhibitors CRT0066101 and CID755673 inhibit several distinct aspects of osteoclast formation. Treating bone marrow macrophages with lower doses of the PKD inhibitors had little effect on M-CSF + RANKL-dependent induction into committed osteoclast precursors, but inhibited their motility and subsequent differentiation into multinucleated mature osteoclasts, whereas higher doses of the PKD inhibitors induced apoptosis of the preosteoclasts. Treating post-fusion multinucleated osteoclasts with the inhibitors disrupted the osteoclast actin belts and impaired their resorptive activity. In conclusion, these data implicate PKD kinases as positive regulators of osteoclasts, which are essential for multiple distinct processes throughout their formation and function.

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Function and Regulation of Protein Kinase D in Oxidative Stress: A Tale of Isoforms

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2138502 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Mathias Cobbaut ◽

Johan Van Lint

Keyword(s):

Oxidative Stress ◽

Protein Kinase ◽

Neurological Disorders ◽

Redox Balance ◽

Protein Kinase D ◽

Oxygen Species ◽

Downstream Effectors ◽

Cancer Cell Survival ◽

Cellular Phenotypes ◽

And Function

Oxidative stress is a condition that arises when cells are faced with levels of reactive oxygen species (ROS) that destabilize the homeostatic redox balance. High levels of ROS can cause damage to macromolecules including DNA, lipids, and proteins, eventually resulting in cell death. Moderate levels of ROS however serve as signaling molecules that can drive and potentiate several cellular phenotypes. Increased levels of ROS are associated with a number of diseases including neurological disorders and cancer. In cancer, increased ROS levels can contribute to cancer cell survival and proliferation via the activation of several signaling pathways. One of the downstream effectors of increased ROS is the protein kinase D (PKD) family of kinases. In this review, we will discuss the regulation and function of this family of ROS-activated kinases and describe their unique isoform-specific features, in terms of both kinase regulation and signaling output.

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Regulation and Function of Protein Kinase D Signaling

Protein Kinase C in Cancer Signaling and Therapy ◽

10.1007/978-1-60761-543-9_7 ◽

2010 ◽

pp. 117-154 ◽

Cited By ~ 1

Author(s):

Enrique Rozengurt

Keyword(s):

Protein Kinase ◽

Protein Kinase D ◽

And Function

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

Biomolecules ◽

10.3390/biom11030483 ◽

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.

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Spatial control of actin-based motility through plasmalemmal PtdIns(4,5)P2-rich raft assemblies.

Biochemical Society Symposium ◽

10.1042/bss0720119 ◽

2005 ◽

Vol 72 ◽

pp. 119-127 ◽

Cited By ~ 19

Author(s):

Tamara Golub ◽

Caroni Pico

Keyword(s):

Protein Kinase ◽

Cell Surface ◽

Actin Cytoskeleton ◽

Lipid Rafts ◽

Patch Clustering ◽

Pkc Protein Kinase C ◽

Membrane Bound ◽

And Function ◽

Cytoskeleton Dynamics ◽

Syndrome Protein

The interactions of cells with their environment involve regulated actin-based motility at defined positions along the cell surface. Sphingolipid- and cholesterol-dependent microdomains (rafts) order proteins at biological membranes, and have been implicated in most signalling processes at the cell surface. Many membrane-bound components that regulate actin cytoskeleton dynamics and cell-surface motility associate with PtdIns(4,5)P2-rich lipid rafts. Although raft integrity is not required for substrate-directed cell spreading, or to initiate signalling for motility, it is a prerequisite for sustained and organized motility. Plasmalemmal rafts redistribute rapidly in response to signals, triggering motility. This process involves the removal of rafts from sites that are not interacting with the substrate, apparently through endocytosis, and a local accumulation at sites of integrin-mediated substrate interactions. PtdIns(4,5)P2-rich lipid rafts can assemble into patches in a process depending on PtdIns(4,5)P2, Cdc42 (cell-division control 42), N-WASP (neural Wiskott-Aldrich syndrome protein) and actin cytoskeleton dynamics. The raft patches are sites of signal-induced actin assembly, and their accumulation locally promotes sustained motility. The patches capture microtubules, which promote patch clustering through PKA (protein kinase A), to steer motility. Raft accumulation at the cell surface, and its coupling to motility are influenced greatly by the expression of intrinsic raft-associated components that associate with the cytosolic leaflet of lipid rafts. Among them, GAP43 (growth-associated protein 43)-like proteins interact with PtdIns(4,5)P2 in a Ca2+/calmodulin and PKC (protein kinase C)-regulated manner, and function as intrinsic determinants of motility and anatomical plasticity. Plasmalemmal PtdIns(4,5)P2-rich raft assemblies thus provide powerful organizational principles for tight spatial and temporal control of signalling in motility.

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