General Signal Transduction

Signal transduction: process where a cell responds to external signals.

Basic steps:

Ligand binds receptor → receptor undergoes conformational change.

Receptor dimerizes (two receptor molecules join together).

Cross-phosphorylation (each receptor phosphorylates the other).

Activated receptor triggers a kinase cascade (series of kinases activating the next).

Kinase = enzyme that phosphorylates other proteins.

Phosphatase = enzyme that removes phosphate groups (deactivates signaling).

Feedback loops possible: signals can be dampened, enhanced, or made oscillatory.

Epidermal Growth Factor (EGF) Pathway

EGF (ligand) binds to its receptor EGFR (a receptor tyrosine kinase).

EGFR dimerizes and phosphorylates itself → activates downstream signaling.

Key outcomes of EGF pathway activation:

Cell Division (mitosis)

Pathway: RAS → RAF → MEK → ERK.

ERK translocates to nucleus and activates transcription factors for proliferation.

Cell Growth

Increases biosynthesis → prepares cell for division.

Cell Survival

PI3K → AKT pathway → prevents programmed cell death (apoptosis).

Relevance to disease:

Overactive EGFR signaling is a hallmark of many cancers.

Hyperactivation leads to excessive proliferation and avoidance of apoptosis.

MAPK/ERK Pathway

Also called Ras-Raf-MEK-ERK pathway.

MAPK = “Mitogen-Activated Protein Kinase.”

Activated by mitogens (signals that trigger mitosis).

Steps:

Ras activates Raf.

Raf phosphorylates MEK.

MEK phosphorylates ERK.

ERK enters nucleus → drives gene expression for division.

Clinical importance:

Pathway is often mutated in cancers.

RAS mutations = common in pancreatic and colorectal cancers.

RAF mutations also common (e.g., BRAF in melanoma).

RAS Function

RAS is a molecular switch, not a kinase.

Switches between active (GTP-bound) and inactive (GDP-bound) forms.

Activation/inactivation cycle:

GEF (e.g., SOS): promotes GDP → GTP exchange, turning Ras ON.

GAP (e.g., NF1): stimulates Ras’s GTPase activity (GTP → GDP), turning Ras OFF.

Mutations and effects:

Mutations at amino acids 12 & 13 → prevent GTP hydrolysis → Ras stuck ON → constant signaling → cancer.

Defects:

Loss of SOS → Ras never turns on → signaling failure (no cancer).

Loss of NF1 (a GAP) → Ras can’t turn off → hyperactivation (cancer).

Mutation blocking GTPase activity → Ras permanently ON (cancer).

RAF and Downstream Signaling

Ras directly activates Raf by physical contact.

Raf is a kinase that starts the phosphorylation cascade.

Raf phosphorylates MEK → MEK phosphorylates ERK.

ERK drives transcriptional changes → proliferation and survival.

Diagram interpretation (from class):

Red = Raf.

Blue = Ras.

Purple = MEK.

Ras activates Raf → Raf activates MEK → MEK activates ERK.