Key Cell Signaling Pathways

Why This Matters

Cell signaling pathways are the language cells use to communicate—and understanding this language is central to nearly every topic you'll encounter in cell biology. These pathways connect directly to exam concepts like signal transduction, gene regulation, cell cycle control, and disease mechanisms. When you see questions about how hormones trigger cellular responses, why cancer cells divide uncontrollably, or how the immune system coordinates attacks, you're really being tested on your understanding of these core signaling mechanisms.

The key insight here is that cells don't just "receive signals"—they amplify, integrate, and translate them into specific actions. Each pathway you learn represents a different strategy for converting an extracellular message into an intracellular response. Don't just memorize pathway names and components—know what type of signal each pathway handles, how it amplifies that signal, and what cellular outcomes it produces. That conceptual framework will serve you far better than rote memorization on exam day.

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Second Messenger Systems

These pathways use small, rapidly diffusing molecules to amplify signals inside the cell. The key principle: one receptor activation can generate thousands of second messenger molecules, creating massive signal amplification.

cAMP Signaling Pathway

• Cyclic AMP (cAMP) is produced by adenylate cyclase when GPCRs activate stimulatory G proteins—this is the classic example of second messenger amplification
• Protein kinase A (PKA) is the primary effector, phosphorylating targets that regulate metabolism, gene expression, and ion channel activity
• Phosphodiesterase enzymes break down cAMP, providing a built-in "off switch" that makes this pathway highly reversible and tunable

Calcium Signaling Pathway

• $Ca^{2+}$ ions function as second messengers released from the endoplasmic reticulum or entering through plasma membrane channels—concentrations can spike 10-100 fold within milliseconds
• Calmodulin is the primary calcium sensor, changing shape when bound to $Ca^{2+}$ and activating downstream kinases like CaMK
• Dysregulation of calcium homeostasis underlies cardiac arrhythmias, neurodegeneration, and muscle disorders—expect disease-connection questions

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Receptor Tyrosine Kinase Cascades

RTKs are enzyme-linked receptors that activate when ligands cause them to dimerize. The defining feature: the receptor itself has kinase activity and phosphorylates downstream targets directly.

Receptor Tyrosine Kinase (RTK) Signaling

• Ligand binding triggers dimerization and autophosphorylation—the receptor phosphorylates itself, creating docking sites for signaling proteins
• Growth factors like EGF, PDGF, and insulin are classic RTK ligands that regulate cell growth, differentiation, and metabolism
• Oncogenic mutations in RTKs (like HER2 in breast cancer) cause constitutive activation—this is a high-yield cancer biology connection

MAPK/ERK Pathway

• Three-tiered kinase cascade: MAPKKK → MAPKK → MAPK (ERK)—each level phosphorylates and activates the next, providing signal amplification at every step
• ERK translocates to the nucleus to phosphorylate transcription factors, directly linking growth factor signals to gene expression changes
• Ras protein initiates this cascade and is mutated in ~30% of human cancers—know this as a classic example of oncogene activation

PI3K-Akt Pathway

• PI3K converts $PIP_2$ to $PIP_3$ at the membrane, recruiting Akt (also called PKB) for activation—this is a lipid-based signaling mechanism
• Akt promotes survival by phosphorylating and inhibiting pro-apoptotic proteins like BAD, while activating mTOR for protein synthesis
• PTEN tumor suppressor reverses PI3K action—PTEN loss is one of the most common events in cancer progression

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G Protein-Coupled Receptor Pathways

GPCRs are the largest family of cell surface receptors, characterized by their seven-transmembrane structure. They work indirectly through heterotrimeric G proteins that act as molecular switches.

G Protein-Coupled Receptor (GPCR) Signaling

• Seven-transmembrane receptors activate heterotrimeric G proteins ($G_α$, $G_β$, $G_γ$) that exchange GDP for GTP upon receptor activation
• $G_α$ subunits determine downstream effects: $G_s$ stimulates adenylate cyclase, $G_i$ inhibits it, and $G_q$ activates phospholipase C
• ~800 human GPCRs detect hormones, neurotransmitters, light, and odors—this diversity makes them targets of ~35% of FDA-approved drugs

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Cytokine and Growth Factor Pathways

These pathways respond to secreted signaling molecules that coordinate responses across tissues. They're especially important for immune function and developmental processes.

JAK-STAT Signaling Pathway

• Cytokine receptors lack intrinsic kinase activity but associate with Janus kinases (JAKs) that phosphorylate each other and the receptor upon ligand binding
• STAT proteins dock at phosphorylated receptors, get phosphorylated by JAKs, then dimerize and translocate to the nucleus as active transcription factors
• Interferons and interleukins signal through this pathway—essential for hematopoiesis and immune responses, and targeted by drugs for autoimmune diseases

TGF-β Signaling Pathway

• TGF-β receptors are serine/threonine kinases that phosphorylate Smad proteins (specifically Smad2/3), which then bind Smad4
• Smad complexes enter the nucleus to regulate genes controlling cell cycle arrest, differentiation, and extracellular matrix production
• Dual role in cancer: TGF-β suppresses early tumors but promotes metastasis in advanced cancer—this context-dependent behavior is frequently tested

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Developmental Signaling Pathways

These pathways are essential for embryonic development and tissue maintenance. They often involve direct cell-cell contact or short-range signaling, and their dysregulation frequently causes cancer.

Wnt Signaling Pathway

• Wnt ligands bind Frizzled receptors, inhibiting the destruction complex that normally degrades β-catenin—this allows β-catenin to accumulate
• β-catenin translocates to the nucleus and partners with TCF/LEF transcription factors to activate genes for proliferation and stem cell maintenance
• APC tumor suppressor is part of the destruction complex—APC mutations cause familial adenomatous polyposis and most sporadic colon cancers

Notch Signaling Pathway

• Juxtacrine signaling: requires direct cell-cell contact between Notch receptor and Delta/Jagged ligands on adjacent cells—no diffusible signal involved
• Proteolytic cleavage releases the Notch intracellular domain (NICD), which enters the nucleus to activate target genes directly
• Lateral inhibition during development: Notch signaling allows one cell to "tell" its neighbors to adopt a different fate—critical for neurogenesis and somite formation

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Quick Reference Table

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Self-Check Questions

1. Which two pathways both use second messengers for signal amplification, and how do their mechanisms differ?

2. A mutation causes a receptor tyrosine kinase to dimerize without ligand binding. Which downstream pathways would be constitutively activated, and what cellular consequences would you predict?

3. Compare and contrast how JAK-STAT and TGF-β/Smad pathways get transcription factors into the nucleus. What type of phosphorylation does each use?

4. Why does the Notch pathway require direct cell-cell contact while Wnt signaling does not? How does this difference relate to their developmental functions?

5. If an FRQ asks you to explain how a single hormone molecule can trigger a large cellular response, which pathways would provide the best examples of signal amplification, and what specific mechanisms would you describe?