Lecture 7 - Regulation of signalling

Today's lecture concludes the self-signaling block.
Learning objectives:
- Describe and compare regulatory mechanisms in cell signaling.
- Design mechanisms for pathways to affect outcomes.
Review of previous topics:
- Cytoskeleton remodeling and migrating cells.
- Core structure of signaling pathways: extracellular signal, receptor, signal relay molecules leading to effects.

Signaling pathways require additional layers of regulation to prevent constant signaling or division.
- Focus of today's lecture:
- Amplification of signals.
- Signal termination (turning pathways off).
- Integration of multiple signaling pathways.

Definition: Positive feedback loops are systems where a process activates itself further upstream.
Example of a simple feedback loop:
- Stimulus activates Protein A.
- Protein A activates Protein B.
- Protein B feeds back to activate Protein A.
In cell signaling context:
- Upstream and downstream terminology:
- Upstream: Closer to the signal/ligand.
- Downstream: Closer to the effect/output.
Specific example with kinases:
- An inactive Kinase E is activated by a signaling kinase, which phosphorylates it, making it active.
- Active Kinase E can phosphorylate itself to maintain activity.
All-or-nothing response:
- Once activated, the pathway continues independently of the signaling input.
- Example: Calcium-induced calcium release enhances signaling, leading to a large cellular response via positive feedback.
- Increased cytosolic calcium opens more calcium channels and maintains signaling.

Definition: Negative feedback loops shorten signaling duration or reduce amplitude.
Example:
- Stimulus activates Protein A, which activates Protein B.
- Protein B negatively feedbacks to inhibit Protein A.
Example with kinases:
- Kinase E is activated by an upstream signal and can phosphorylate a phosphatase.
- The active phosphatase removes the phosphate from Kinase E, turning it off.
Effects of negative feedback loops:
- Short delay leads to lower signaling amplitude.
- Longer delays can lead to oscillatory signaling behavior.
- Pathways can reach new steady states based on balance of activation and inhibition.
Receptor internalization is a form of negative feedback:
- Ligand binding can lead to receptor internalization, stopping downstream signaling despite the continued presence of the ligand.

Cells receive multiple signaling pathways concurrently.
Mechanisms of integration:
- Positive and negative feedback loops.
- Crosstalk between pathways.
- Changes in signaling based on context (e.g., high vs. low concentrations of ligands.)
Example:
- Combines different signals predicting varying output: survival, division, or differentiation.

Scaffold Proteins:
- Increase signaling speed and specificity by bringing signaling molecules together.
Lipid Rafts:
- Membrane microdomains enrich certain proteins, aiding in fast signaling.
- Cholesterol plays a key role in raft formation and efficacy.
Compartmentalization:
- Structures like cilia can concentrate and isolate receptors, speeding up signal encounters.
Example: The hedgehog signaling pathway showcases these mechanisms effectively.
- Hedghog binds to Patched receptor which relieves inhibition on smoothened protein, promoting signaling as unbound smoothened traffics into plasma membrane.

Different receptors activated by the same ligand can yield varying responses based on cell type.
Example:
- Adrenergic receptors respond differently to adrenaline (alpha, beta, alpha II).
- Their activation leads to dissimilar cellular effects (muscle contraction vs inhibition).
Combination of receptor types influences overall cellular behavior and responses to external signals.

Tomorrow discussion will focus on studying outputs of signaling pathways.
Reminder about workshop and discussions for clarifications on the content covered.