Diacylglycerol signaling pathway

05/02/2023by Yonas Teshom

e

1

DIACYLGLYCEROL SIGNALING PATHWAY PREPARED BY YONAS TESHOME DEPARTMENT OF MEDICAL PHYSIOLOGY 4/28/2016

05/02/2023by Yonas Teshome

2 Outline

Objectives Introduction Dawn stream effectors of DAG PKC induced cellular processes The DGK, RasGRP, PKD, Chimaerins, and Munc 13 Summary Reference


3 Objectives

At the end of this session you will be able to: Define diacylglycerol Describe the signaling pathways of diacyleglycerol List the down stream effectors of DAG and List some of the cellular processes takes place by DAG through PKC


4 Introduction

Diacylglycerol (DAG) is a lipid signal messenger which is an essential second messenger in mammalian cells.

Is glycerol derivative that have two hydroxyl groups esterified by fatty acids.

R and R' are saturated or unsaturated hydrocarbon chains


5Cont...

Key enzymes in most of the signaling processes that generate DAG are the phosphatidylinositol 4,5-bisphosphate- specific phospholipase C isozymes.

Hydrolysis of Phosphatidyl inositol 4,5 bisphosphate (PIP2) by PLC causes the formation of DAG and inositol 1,4,5-trisphosphate (IP3).

In compared to IP3, DAG is very nonpolar molecule therefore it remain in the membrane while IP3 is released into cytosol.

In addition, DAGs are produced from phosphatidylcholine (PC) by two subsequent reactions involving two mammalian PC-specific phospholipase D isozymes (PCPLDs) and phosphatidic acid phosphohydrolase.


6Cont…


7 Cont…

The most prominent downstream effector of diacylglycerol and the functionally analogous phorbol esters belong to the protein kinase C family, but at least five alternative types are known:

Protein kinase D, RasGRPs, Chimaerins, and Munc13s.

These can functions independently of protein kinase C isozymes, and regulates processes as diverse as gene transcription, lipid signaling, cytoskeletal dynamics, intracellular membrane trafficking, or neurotransmitter release.


8 Signaling pathway through PKC

Protein kinase C is a family of protein kinase enzymes that are involved in controlling the function of other proteins through phosphorylation.

They are divided into three subfamilies, based on their second messenger requirements: Conventional (c)PKCs contain the isoforms α, βI, βII, and γ. These require

Ca2+, DAG, and a phospholipid such as phosphatidylserine for activation. Novel (n)PKCs include the δ, ε, η, and θ isoforms, and require DAG, but do

not require Ca2+ for activation. Atypical (a)PKCs includes ζ and λ isoforms.


9Cont…


10 PKC signaling induced cellular processes

PKC is involved in regulation of diverse cellular processes including proliferation, differentiation, neural development, synaptic transmission, axonal regeneration, smooth muscle contraction, gene expression, etc.

Example: Cell proliferation by PKC signaling Activation of PKC induces phosphorylation of transcription factor serum

response factor (SRF). SRF regulates immediate early genes (IEGs) such as Egr-1 (early growth

response gene 1) that control cell proliferation. Immediate early genes with proteins such as c-jun, c-fos, myc which are

transcription factors and activate target gene resulting in cell proliferation.


11Acute stress

HypoxiaIschemia

Chronic stressAtherosclerosis

Restenosis

PKCβ Egr-1

Cytokines, ChemokinesProcoagulant molecules

Adhesion molecules

Inflammation, Migration, Proliferation

Vascular dysfunctionTissue injury

Example 2 PKCβ – Egr-1 in vascular stress response


12cont…

PKCθ plays important roll in T cell activation by activating Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kβ), activator protein 1(AP1), Nuclear factor activating T cell (NFAT), T cell proliferation by IL2( inter leukin 2), Cell apoptosis by FasL.

PKC is anchored to membrane by specific proteins often localized to specific subcellular sites. This PKC anchoring proteins are named receptors for activated C kinases (RACKs).

Therefore cells often regulates PKC effect according to their need by RACKs.

Cell type.docx


13 Other down stream effectors of DAG

Protein kinase Ds The PKD family in mammals consists of PKD1, PKD2, and PKD3.

All PKDs contain two C1 domains, a negatively charged central domain, a pleckstrin homology (PH) domain, and a serine/threonine protein kinase catalytic domain. PKD1 contains an additional amino-terminal apolar domain.

The major PKD activation mechanism involves phosphorylation by PKCα, PKCε, and PKCη at sites in the regulatory domain


14Cont….


15Cont…

PKD regulate processes like signal transduction, membrane trafficking, and cell survival, migration, differentiation, and proliferation.


16Cont…

Through their RasGEF domains, most RasGRPs(Ras guanyl nucleotide-releasing protein) promote GDP/GTP exchange and activation of Ras and related small GTPases, which leads to the stimulation of the Raf-MEK-ERK cascade and to the regulation of other signaling pathways.

Through activation of the Raf-MEK-ERK pathway, RasGRPs have been implicated in cell differentiation, cell proliferation, cell transformation, T-cell receptor signaling, T cell differentiation, B-cell receptor signaling, and neuronal differentiation.


17Cont…

Chimaerins the first high affinity non-PKC DAG/PE receptors discovered, By inactivating Rac, necessarily interfere with all downstream effects of Rac (e.g. formation of lamellipodia and membrane ruffles, and loss of stress fibers).

Generally, chimaerins are implicated in diverse cellular processes such as cell adhesion, cytoskeletal dynamics, lamellipodia/ filopodia formation, phagocytosis, and cell proliferation.


18Cont…

Munc13s act by unfolding and activating the soluble N-ethyl maleimide sensitive factor attachment protein receptor (SNARE) protein Syntaxin and thereby promoting SNARE complex formation and secretory vesicle priming.

Munc13s rather than PKCs are the only functionally relevant DAG sensitive presynaptic regulators of transmitter release. Similarly, insulin secretion from pancreatic b cells is increased by Munc13 action in experiment.


19 Regulation of DAG

DAG kinases phosphorylate DAG to form phosphatidic acid. DAG kinases have a major role in intracellular signaling in which

they terminate the DAG signal generated by PLCs and form phosphatidic acid, which itself is a signaling molecule.

DAG kinases are thought to be active only in spatially restricted compartments following physiological DAG generation.

One such subcellular compartment is the cytoskeleton where DAG kinases might regulate cytoskeletal dynamics by producing phosphatidic acid, which would affect actin capping proteins and actin polymerization.


20

In addition, DAGkinase dependent regulation of DAG and phosphatidic acid levels affect GTPase activating proteins for Rho family members and certain DAG kinases interact directly with Rho GTPase.

DAG kinases(α,β,γ) are also constitutively localized in or recruited to nuclear compartments where they are thought to regulate a strictly compartmentalized DAG signaling pathway that controls cell proliferation.


21 Summary

DAG is an essential second messenger in mammalian cells. DAG is formed by hydrolysis of PIP2 by an enzyme called PLC. Intracellular targets of DAG are: Protein kinase C, Protein kinase D, RasGRPs,

Chimaerins, and Munc13s. As a second messenger DAG signals diverse cellular processes including

proliferation, differentiation, neural development, synaptic transmission, axonal regeneration, smooth muscle contraction, gene expression, etc.

DAG kinases have a major role in intracellular signaling in which they terminate the DAG signal generated by PLCs with receptors for activated C kinases (RACKs).


22 References

N. Brose, A. Betz and H. Wegmeyer, Divergent and convergent signaling by the diacylglycerol second messenger pathway in mammals

Yukiko K. Kaneko* and T. Ishikawa, Diacylglycerol Signaling Pathway in Pancreatic β-Cells: An Essential Role of Diacylglycerol Kinase in the Regulation of Insulin Secretion, Shizuoka 422–8526, Japan. Received January 20, 2015

https://en.wikipedia.org/wiki/Protein_kinase_C


23 THE END!

THANK YOU

Health & Medicine

Diacylglycerol signaling pathway