Cell Growth and Signaling Pathways

Cells decide whether to grow based on environmental conditions.
Growth factors are signaling molecules that help cells control growth.
Cells must decide whether to stay in G0 phase or enter the cell cycle.
The decision to grow is a community decision, requiring input from neighboring cells.

Cell A secretes Egf Ligand (epidermal growth factor) to stimulate growth in other cells.
Egf is a protein.
Examples of growth factors: Ngf (nerve growth factor), Pdgf (platelet-derived growth factor).
Egf and other growth factors are important in many parts of the body, not just the areas for which they are named.

Cell B has an Egf receptor specific to the Egf Ligand.
Egfr protein is specific to the Egf Ligand.
Specific receptors exist for specific ligands, with some cross-reactivity possible.
Cell A can direct specific cells in the neighborhood to grow without affecting others.
Example: skin wound leading to secretion of epidermal growth factor, causing keratinocytes to divide.
Same ligand can trigger different responses in different cell types.

Cells grown on polystyrene plastic in a culture medium.
Culture medium provides osmotic balance and energy to prevent them from drying out.
Without growth factors, cells will remain without cell division.
Cancer cells often used due to their rapid growth.
Normal cells require growth factors to divide in culture.

Adding serum to the culture medium induces cell division.
Serum is derived from blood.
To make serum, blood is allowed to coagulate, and the clotted blood and other cells are filtered out leaving the serum.
Blood clots when platelets are exposed to tissue factor outside the bloodstream.
Activated platelets stick together and burst open, initiating the blood clotting process.
Platelets secrete Factor 8 and growth factors.
Serum is rich in growth factors, including Pdgf.
Serum from cows is often used in cell culture, even for human cells.

Cells integrate signals from growth factors and growth inhibitory factors.
Cells in G0 wait for sufficient growth factors before re-entering the cell cycle.
Cells exit G0 and divide upon the addition of serum.
Different classes of receptors exist, including tyrosine kinase receptors and G protein receptors.

Example to demonstrate cell signaling (Egf receptor).
Cell membrane consists of a lipid bilayer with hydrophilic heads and hydrophobic tails.
Proteins sitting in the hydrophobic region have a hydrophobic transmembrane domain.
Outside the cell, the receptor domain binds to ligands like Egf.
Multiple receptors are needed.

On the inside of the cell, the intracellular domain has enzymatic activity.
When Egf binds, it helps two Egf receptors bind to it, bringing them close together to form a dimer.
When receptors dimerize, their intracellular domains get close together.
These intracellular domains cross-phosphorylate each other, adding phosphate groups to the target protein.
If a protein is phosphorylated by a kinase, the protein will turn on. If a protein is dephosphorylated by a phosphatase, the protein will turn off. Phosphorylation makes the protein switch between on and off. This is case dependent and depends on the protein itself.
Tyrosine kinase receptors phosphorylate tyrosine amino acids.
Phosphorylation turns on the receptor, allowing it to dock with additional enzymes.

Activated Egf receptor can trigger the Ras signaling pathway.
Ras has an intracellular domain and a hydrophobic transmembrane domain.
Inactive Ras becomes active through Gtp exchange.
Inactive Ras has GDP (diphosphate), while active Ras has Gtp (triphosphate).
Activated Egf receptor binds to an interface piece that causes Gdp to be exchanged for Gtp, activating Ras.

Active Ras can trigger the Map Kinase pathway.
Active Ras phosphorylates a protein, which then phosphorylates another protein, and so on.
The final protein is a kinase that can activate proteins and initiate transcription.
Map kinase is activated by map kinase kinase, which is activated by map kinase kinase kinase.
This series of phosphorylation steps is a signaling cascade.

Relaying information from one side of the cell to the other (e.g., Egf receptor to map kinase).
Amplification: Each activated protein can activate multiple targets, leading to a stronger signal.
Transduction: Changing the form of the signal (e.g., from Egf protein to Ras to map kinase).
Distribution: One protein can do multiple things, such as activate proteins and initiate transcription.
Integration: Integrating information from different signals, such as Pdgf and Tgf beta.