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Cell Biology Unit 6: Cell Signaling

This unit explains how cells detect external signals and convert them into internal responses through receptors, second messengers, molecular switches and kinase cascades.

Covers: Types of signaling and receptor binding, Intracellular (nuclear) receptors, G-protein-coupled receptors and second messengers, Receptor tyrosine kinases, Ras and MAP kinase, PI 3-kinase–Akt and JAK–STAT pathways, Notch and Wnt, Signal amplification, termination and desensitization

Study guide

Cells signal in several ways. Endocrine hormones travel in the blood, paracrine signals act on nearby cells, autocrine signals act on the cell that made them, and contact-dependent (juxtacrine) signals need direct membrane contact, as in Notch. Each signal binds a specific receptor. Binding follows simple equilibrium: the fraction of receptors occupied is [L]/([L] + Kd), so half are bound when [L] equals Kd. Small hydrophobic signals such as steroid and thyroid hormones cross the membrane and bind intracellular nuclear receptors that act as transcription factors. Hydrophilic signals bind cell-surface receptors: ion-channel-linked, G-protein-coupled, or enzyme-linked receptors.

G-protein-coupled receptors (GPCRs) span the membrane seven times. Ligand binding lets the receptor act as a GEF for a heterotrimeric G protein: Gα releases GDP, binds GTP and separates from Gβγ. Gαs activates adenylyl cyclase, which makes cAMP; cAMP binds the regulatory subunits of PKA and releases its catalytic subunits. Gαi inhibits adenylyl cyclase. Gαq activates phospholipase C, which splits PIP₂ into IP₃ and DAG; IP₃ releases Ca²⁺ from the ER, and Ca²⁺ and DAG activate PKC, while Ca²⁺ also binds calmodulin. Gα turns itself off by hydrolyzing GTP. Cholera toxin locks Gαs on, and pertussis toxin blocks Gαi.

Receptor tyrosine kinases (RTKs) such as the EGF and insulin receptors dimerize on ligand binding and phosphorylate each other's tyrosines. The phosphotyrosines dock proteins with SH2 domains. Grb2 brings the GEF Sos to the membrane, which turns on Ras by GDP-to-GTP exchange. Ras-GTP activates the MAP kinase cascade Raf → MEK → ERK, and ERK enters the nucleus to activate genes for growth and division. GAPs switch Ras off. RTKs also activate PI 3-kinase, which makes PIP₃; PIP₃ recruits Akt, which promotes survival and growth, and the phosphatase PTEN reverses it. Cytokine receptors use associated JAK kinases that phosphorylate STAT transcription factors.

Some pathways use regulated proteolysis. In Notch signaling, a Delta ligand on one cell binds Notch on a neighbor, triggering cleavages, the last by γ-secretase, that free the Notch intracellular domain to enter the nucleus. In Wnt signaling, a destruction complex of APC, axin and GSK3 normally phosphorylates β-catenin, marking it for degradation; Wnt binding to Frizzled inhibits this complex, so β-catenin builds up and activates genes. Mutations in APC cause most colon cancers. Gases such as nitric oxide diffuse into neighboring cells and activate guanylyl cyclase directly.

Signaling pathways amplify, integrate and end signals. Each enzyme in a cascade activates many copies of the next component, so a few hormone molecules can produce a huge response. Signals end when G proteins and Ras hydrolyze GTP, phosphodiesterases destroy cAMP, phosphatases remove phosphates, and Ca²⁺ is pumped away. Long exposure causes desensitization: GRKs phosphorylate active GPCRs, and arrestins block G protein coupling and trigger receptor endocytosis. Cells respond differently to the same signal depending on which receptors and downstream proteins they express. Mutations that lock switches on, such as oncogenic Ras, cause signaling to continue without a ligand.

Key ideas

• Receptor occupancy depends on ligand concentration relative to Kd.
• Hydrophobic signals bind intracellular receptors; hydrophilic signals bind surface receptors.
• GPCRs activate heterotrimeric G proteins that control second messengers such as cAMP, IP₃, DAG and Ca²⁺.
• RTKs dimerize and phosphorylate tyrosines that recruit SH2 proteins and activate Ras and PI3K.
• GTPases such as Gα and Ras are molecular switches turned on by GEFs and off by GTP hydrolysis with GAPs.
• Kinase cascades amplify signals, and phosphatases, phosphodiesterases and arrestins end them.
• The same ligand can trigger different responses in cells with different receptors.

Formulas and rules

Common mistakes

• Saying GEFs turn GTPases off; GEFs turn them on and GAPs turn them off.
• Mixing up cholera toxin (Gαs stuck on) with pertussis toxin (Gαi blocked).
• Thinking steroid hormones bind cell-surface receptors.
• Adding instead of multiplying the gains of a cascade.
• Forgetting that IP₃ releases Ca²⁺ from the ER, not from outside the cell.

Before the test, make sure you can

• Classify signals as endocrine, paracrine, autocrine or contact-dependent.
• Calculate receptor occupancy from ligand concentration and Kd.
• Trace GPCR pathways through Gs, Gi and Gq to their second messengers and kinases.
• Trace RTK signaling through Ras–MAPK and PI3K–Akt.
• Explain how GEFs, GAPs, phosphodiesterases, phosphatases and arrestins control signals.
• Describe Notch, Wnt and JAK–STAT pathways.
• Predict the effects of toxins, drugs and mutations on a pathway.
• Calculate amplification in a signaling cascade and order pathway components using epistasis.

Words to know

Endocrine signaling

Hormones released into the blood act on distant target cells.

Paracrine signaling

Local mediators act on nearby cells.

Kd

The ligand concentration at which half the receptors are occupied; lower Kd means tighter binding.

Nuclear receptor

An intracellular receptor for hydrophobic signals that acts as a ligand-activated transcription factor.

GPCR

A seven-pass transmembrane receptor that activates heterotrimeric G proteins.

Heterotrimeric G protein

A Gα, Gβ and Gγ complex in which Gα binds GDP (off) or GTP (on).

Adenylyl cyclase

A membrane enzyme that makes cAMP from ATP.

PKA

Protein kinase A, activated when cAMP binds and releases its regulatory subunits.

Phospholipase C

An enzyme that cleaves PIP₂ into IP₃ and DAG.

Receptor tyrosine kinase

An enzyme-linked receptor that dimerizes and phosphorylates tyrosines when ligand binds.

SH2 domain

A protein domain that binds specific phosphotyrosine sites.

Ras

A small GTPase that relays RTK signals to the MAP kinase cascade.

GEF

Guanine nucleotide exchange factor; activates a GTPase by swapping GDP for GTP.

GAP

GTPase-activating protein; inactivates a GTPase by speeding GTP hydrolysis.

MAP kinase cascade

A three-kinase relay (MAPKKK → MAPKK → MAPK), such as Raf → MEK → ERK.

Akt

A kinase recruited by PIP₃ that promotes cell survival and growth.

Arrestin

A protein that binds phosphorylated GPCRs to stop G protein activation and trigger endocytosis.

β-catenin

A protein stabilized by Wnt signaling that enters the nucleus to activate target genes.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.