Signalling pathways in Apoptosis.pptx (2)

Apoptosis is a unique form of cell death characterized by an orderly, gene-dependent process of cell disintegration.
It is an essential life process in metazoan animals, contributing critically to the formation and functionality of tissues and organs.
Particularly significant in adults, apoptosis plays a vital role in the immune system's proper functioning.

Major Pathways of Apoptotic Cell Death Induction:
- Extrinsic Pathway: Signaling through death receptors leading to the formation of the death-inducing signaling complex (DISC).
- Intrinsic Pathway: Mainly mediated through mitochondria, which leads to the formation of the apoptosome.

Apoptosis maintains a balance between cell death and division.
Failure to undergo apoptosis can result in uncontrolled cell proliferation, which may lead to diseases such as cancer.

Caspase Family Role:
- Initiator caspases (caspases 8, 9) and executioner caspases (caspases 3, 6, 7) are critical in apoptosis.
- Caspases exist initially as inactive monomers (procaspases), which dimerize and activate upon receiving apoptotic signals.

Initiator caspases possess a protease domain and a small protein interaction domain.
Activation occurs through the assembly of adaptor proteins, leading to initiator caspases' dimerization and subsequent cleavage of specific sites in their protease domains.
Rearrangement occurs post-cleavage, resulting in large and small subunits that further activate executioner caspases.

Executioner Caspases are initially inactive dimers.
Cleavage by initiator caspases results in conformational changes, activating them to cleave essential proteins, driving the cell to death.

Activation of the Extrinsic Pathway:
- Triggered by extracellular signal proteins binding to death receptors on cell surfaces.
Death Receptors:
- Transmembrane proteins with ligand-binding domains that activate the apoptotic program, including the TNF receptor family.
Caspase Activation in the Extrinsic Pathway:
- Death receptor clustering induces death domain activation, leading to the recruitment of initiator caspases and formation of the DISC.

Trimeric Fas ligand on killer lymphocytes interacts with Fas receptors on target cells, causing receptor clustering and activation of death domains.
FADD proteins recruited by activated receptors lead to the assembly of DISC, activating caspase-8 and triggering executioner caspases.

Internal Activation of Apoptosis:
- Initiated by intracellular signals due to factors like DNA damage.
- Relies on mitochondria releasing intermembrane proteins into the cytosol, including cytochrome c.
Role of Cytochrome c:
- Binds to Apaf1 to form an apoptosome, which subsequently recruits and activates initiator caspase-9.

Upon apoptosome formation, activated caspase-9 triggers downstream executioner caspases, leading to apoptosis.

Role of Bcl2 Family Proteins:
- Regulate intrinsic apoptosis by controlling the release of cytochrome c and other proteins from mitochondria.
Classes of Bcl2 Family Proteins:
- Anti-apoptotic (e.g., Bcl2, BclX), pro-apoptotic effectors (e.g., Bax, Bak), and BH3-only proteins (e.g., Bad, Bim).

In the absence of an apoptotic stimulus, anti-apoptotic Bcl2 proteins inhibit effector proteins, preventing apoptosis.
In response to stimuli, BH3-only proteins activate effector proteins, promoting the release of mitochondrial intermembrane proteins, triggering apoptosis.

Membrane lipid composition is vital for cellular homeostasis and signaling.
Membrane Asymmetry:
- Eukaryotic membranes display asymmetry in lipid distribution and protein topology, essential for cellular function.

Membrane lipids serve as secondary messengers in cell signaling pathways, notably in the phosphatidylinositol signaling pathway activated by G-protein coupled receptors.
Phospholipase C hydrolyzes PIP2 into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), which act as secondary messengers.