Lecture 3-14: Enzyme-Coupled Receptors

Enzyme-Coupled Receptors

Enzyme-coupled receptors play a key role in cellular signaling.
They either have intrinsic enzymatic activity or recruit other proteins that provide this function.
Commonly involved in signalling pathways related to growth, differentiation, and metabolism.

Most prevalent type of enzyme-coupled receptors.
Activated through ligand-induced dimerization which leads to autophosphorylation on tyrosine residues.
Ligands for RTKs typically exist as dimers; their binding promotes receptor dimerization.
- Dimerization facilitates proximity of kinase domains, allowing phosphorylation and creating specific binding sites for adapter proteins.
Ligand-independent activation can occur through high levels of receptor expression due to mutations in regulatory DNA.

These kinases are another category of enzyme-coupled receptors, though less common than RTKs.
They work similarly by promoting phosphorylation events when activated.

Ras is a monomeric G protein activated by RTKs through Ras-GEF.
Ras-GEF exchanges GDP for GTP on Ras, activating the protein and allowing it to propagate the signal.
The signal persists until Ras-GAP hydrolyzes GTP to GDP, turning Ras off.

Activated Ras initiates MAP kinase cascades, crucial for promoting cell division (mitogenic signals).
Typically involves a sequence of phosphorylation events:
- MAPKKK (e.g., RAF) ➔ MAPKK (e.g., MEK) ➔ MAPK (e.g., ERK) ➔ effector proteins.
Each kinase activates subsequent kinases, forming a phosphorylation cascade.

RTKs can also signal through the PI3K/Akt pathway promoting cell survival.
Upon activation, PI3K converts PIP2 to PIP3, recruiting and activating Akt.
- Akt, once activated, phosphorylates downstream targets, promoting cell growth and inhibiting apoptosis via Bcl2.
This pathway can be terminated by the action of PTEN which converts PIP3 back to PIP2.

Akt signaling helps inhibit apoptosis by activating Bcl2.
In the absence of Akt, Bcl2 is sequestered by Bad, a pro-apoptotic factor.
Akt phosphorylation of Bad releases Bcl2, promoting cell survival.
Akt also activates Tor, promoting protein synthesis and cell growth.
- Rapamycin inhibits Tor, leading to decreased cell growth and energy demands.

Similar signaling events take place in both GPCR (G Protein-Coupled Receptors) and RTK networks.
While mechanisms may differ, many cellular responses are integrated through common pathways.
Components include primary signaling molecules, secondary messengers (like cAMP, Ca2+), and effector proteins that respond to these signals.

A method to study protein interactions and complexes.
Involves isolating specific proteins using antibodies; proteins that interact can be co-precipitated and analyzed via gel electrophoresis.

Use mutations in signaling components to identify binding sites and deduce the order of protein interactions.
Experiments can show relationships among proteins in a signaling pathway, such as Ras acting downstream of Protein X.
Understanding these interactions is critical for developing targeted therapies.

Functions through direct cell-to-cell contact, influencing tissue differentiation.
As one cell becomes a neuron, it expresses the Delta ligand that affects neighboring cells through Notch receptor interaction, preventing their differentiation into neurons.

Examples include cortisol, estradiol, and testosterone, which bind intracellular receptors.
Binding results in conformational changes that allow them to act as transcription factors by affecting gene expression in the nucleus.

While sharing some kinase-based functions from a common ancestor, signaling pathways have diverged significantly between plants and animals.
Ethylene signaling in plants provides a unique example, employing kinase pathways that inhibit transcription, distinct from animal signaling mechanisms.

Understanding enzyme-coupled receptors and their signaling mechanisms is crucial in cell biology, especially RTKs which facilitate key cellular functions, integrating various signals to orchestrate complex biological processes.