Spatio-Temporal Regulation of PKC Isoforms Imparts Signaling Specificity

Mukherjee, Arkajyoti; Roy, Sayoni; Saha, Bhaskar; Mukherjee, Dilip

doi:10.3389/fimmu.2016.00045

Cited by 21 publications

(21 citation statements)

References 53 publications

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“…Among PKC isoforms, classical PKCs (α, β1, β2, γ) and novel PKCs (δ, ε, η, θ) have both C1A and C1B domains in their regulatory domain, and these isoforms can bind 1,2-diacylglycerol. 50 Classical PKCs or novel PKCs, but not atypical PKCs, are predicted to be involved in EP4-mediated fibulin-1 upregulation.…”

Section: Discussionmentioning

confidence: 99%

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus

Ito

Yokoyama

Nakakoji

et al. 2020

ATVB

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Objective: The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1–deficient ( Fbln1 −/− ) mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse ( Ptger4 −/− ) DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively. Conclusions: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.

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Section: Discussionmentioning

confidence: 99%

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus

Ito

Yokoyama

Nakakoji

et al. 2020

ATVB

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“…For example, PMA recruits both cPKCs and nPKCs to the plasma membrane [206]. PKC activators often activate cPKCs isoforms to the greatest degree, then the nPKCs and aPKCs [252]. Also, the DAG analog 1,2-dioctanoyl-sn-glycerol (DiC8) blocks K v , BK Ca and K ATP channels of mesenteric artery VSM in a PKC-independent manner.…”

Section: Protein Kinase Cmentioning

confidence: 99%

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

Liu

Khalil

2018

Biochemical Pharmacology

126

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Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined. Biochemical studies have also suggested that stimulation of Gq protein-coupled membrane receptors activates phospholipase C and promotes the hydrolysis of membrane phospholipids into inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DAG). IP stimulates initial Ca release from the sarcoplasmic reticulum, and is buttressed by Ca influx through voltage-dependent, receptor-operated, transient receptor potential and store-operated channels. In order to prevent large increases in cytosolic Ca concentration ([Ca]), Ca removal mechanisms promote Ca extrusion via the plasmalemmal Ca pump and Na/Ca exchanger, and Ca uptake by the sarcoplasmic reticulum and mitochondria, and the coordinated activities of these Ca handling mechanisms help to create subplasmalemmal Ca domains. Threshold increases in [Ca] form a Ca-calmodulin complex, which activates myosin light chain (MLC) kinase, and causes MLC phosphorylation, actin-myosin interaction, and VSM contraction. Dissociations in the relationships between [Ca], MLC phosphorylation, and force have suggested additional Ca sensitization mechanisms. DAG activates protein kinase C (PKC) isoforms, which directly or indirectly via mitogen-activated protein kinase phosphorylate the actin-binding proteins calponin and caldesmon and thereby enhance the myofilaments force sensitivity to Ca. PKC-mediated phosphorylation of PKC-potentiated phosphatase inhibitor protein-17 (CPI-17), and RhoA-mediated activation of Rho-kinase (ROCK) inhibit MLC phosphatase and in turn increase MLC phosphorylation and VSM contraction. Abnormalities in the Ca handling mechanisms and PKC and ROCK activity have been associated with vascular dysfunction in multiple vascular disorders. Modulators of [Ca], PKC and ROCK activity could be useful in mitigating the increased vasoconstriction associated with vascular disease.

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“…Novel PKC (nPKC: nPKC-δ, -ε, -θ and -η) are activated by DAG, PS, and PMA, however, they are calcium independent. Atypical PKC (aPKC: aPKC-ι, -λ, and -ζ) do not require DAG, calcium, nor PMA for activation [93, 111–113]. The retina expresses various isoforms of PKC.…”

Section: Molecular Mechanisms Of Diabetic Retinopathymentioning

confidence: 99%

Diabetic retinopathy: Breaking the barrier

et al. 2017

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Diabetic retinopathy (DR) remains a major complication of diabetes and a leading cause of blindness among adults worldwide. DR is a progressive disease affecting both type I and type II diabetic patients at any stage of the disease, and targets the retinal microvasculature. DR results from multiple biochemical, molecular and pathophysiological changes to the retinal vasculature, which affect both microcirculatory functions and ultimately photoreceptor function. Several neural, endothelial, and support cell (e.g., pericyte) mechanisms are altered in a pathological fashion in the hyperglycemic environment during diabetes that can disturb important cell surface components in the vasculature producing the features of progressive DR pathophysiology. These include loss of the glycocalyx, blood-retinal barrier dysfunction, increased expression of inflammatory cell markers and adhesion of blood leukocytes and platelets. Included in this review is a discussion of modifications that occur at or near the surface of the retinal vascular endothelial cells, and the consequences of these alterations on the integrity of the retina.

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Spatio-Temporal Regulation of PKC Isoforms Imparts Signaling Specificity

Cited by 21 publications

References 53 publications

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

Diabetic retinopathy: Breaking the barrier

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