AP Biology 4.3-4.4: Signal Transduction and Changes

Signal transduction

Signal transduction is the process by which a physical or chemical stimulus is converted into a series of intracellular molecular events that produce a cellular response.

What is the difference between a ligand, receptor, and second messenger in cell signaling?

A ligand is a signaling molecule, often called a first messenger, that binds a receptor. The receptor detects and transmits the signal, while a second messenger such as $cAMP$, $IP_3$, or $Ca^{2+}$ relays and often amplifies the signal inside the cell.

What happens when a ligand binds an extracellular receptor?

Ligand binding changes the receptor's conformation. The intracellular portion may then activate an enzyme or expose a binding site for signaling proteins, initiating a pathway through the cytoplasm.

Why can the same extracellular signal produce different responses in different cells?

Different cells may express different receptors, signaling proteins, enzymes, transcription factors, or target genes. Internal conditions and interactions with other pathways also influence the final response.

What molecular changes can result from a signal transduction pathway?

Signaling can alter gene transcription, protein translation, protein activity through post-translational modification, protein location, metabolism, cell growth, division, or survival.

Signal amplification

Signal amplification occurs when one activated signaling molecule activates many downstream molecules, allowing a small initial stimulus to produce a large cellular response.

How do intracellular receptors differ from cell-surface receptors?

Intracellular receptors bind ligands that can cross the plasma membrane, such as many lipid-soluble steroid hormones, and often directly regulate gene expression. Cell-surface receptors bind extracellular ligands that generally cannot cross the membrane and transmit the signal through intracellular proteins or second messengers.

Second messenger

A second messenger is a small intracellular signaling molecule produced or released in response to receptor activation. Examples include cyclic AMP ($cAMP$), inositol trisphosphate ($IP_3$), and $Ca^{2+}$.

How can $IP_3$ and $Ca^{2+}$ function in signal transduction?

$IP_3$ can trigger the release of stored $Ca^{2+}$ into the cytoplasm. The increase in cytoplasmic $Ca^{2+}$ activates calcium-binding proteins and enzymes, producing downstream cellular responses.

What is the role of adaptor proteins in signaling pathways?

Adaptor proteins help bring signaling proteins into the correct proximity and organize signaling complexes. They often connect activated receptors to enzymes or downstream effectors without necessarily having enzymatic activity themselves.

How do specialized protein domains help signaling proteins respond to second messengers?

Specific domains bind particular signaling molecules; for example, EF-hand domains bind $Ca^{2+}$ in calmodulin, while pleckstrin homology domains can bind phosphoinositides such as $PIP_3$. Binding can change a protein's conformation, location, or activity.

What is the effect of phosphorylation on a target protein?

Phosphorylation can activate or inhibit a protein by changing its conformation, interactions, or cellular location. Its effect depends on the specific protein and phosphorylation site.

Protein kinase versus protein phosphatase

A protein kinase transfers a phosphate group, usually from ATP, to a target protein. A protein phosphatase removes a phosphate group through dephosphorylation; together, these enzymes reversibly regulate signaling proteins.

G protein-coupled receptor (GPCR)

A GPCR is an integral membrane receptor with seven transmembrane regions that activates a heterotrimeric G protein after ligand binding. The G protein contains $G\alpha$, $G\beta$, and $G\gamma$ subunits.

What sequence of events activates a heterotrimeric G protein after a ligand binds a GPCR?

Ligand binding changes the GPCR's conformation, causing $G\alpha$ to exchange GDP for GTP. Activated $G\alpha$ separates from $G\beta\gamma$, and one or both components interact with downstream effectors such as ion channels or phospholipases.

How does a GPCR signal become amplified?

One ligand-bound receptor can activate multiple G proteins, and each activated G protein can regulate downstream enzymes or channels that affect many additional molecules. Amplification depends on the lifetimes of receptor-ligand and receptor-effector interactions and on how quickly activated components are deactivated.

What mechanisms turn off GPCR signaling?

The activated receptor or downstream proteins can be phosphorylated, and the receptor can undergo $\beta$-arrestin-dependent internalization. GTP hydrolysis by G proteins and degradation of second messengers also terminate the signal.

Receptor tyrosine kinase (RTK)

An RTK is a cell-surface receptor with an extracellular ligand-binding region and an intracellular tyrosine kinase domain. Ligand binding commonly promotes receptor dimerization and phosphorylation of tyrosine residues.

Why is RTK dimerization important for signal transduction?

Ligand-induced dimerization brings two intracellular kinase domains together. They phosphorylate tyrosine residues on one another, or autophosphorylate, creating docking sites and activating downstream signaling proteins.

What is the role of small G proteins such as RAS in RTK signaling?

Activated RTKs recruit or activate exchange factors such as SOS, which promote GTP binding to RAS. GTP-bound RAS acts as a molecular switch that activates downstream pathways including the RAF-MEK-ERK MAP kinase cascade.

What are integrins, and how do they participate in signaling?

Integrins are cell-surface receptors that connect cells to the extracellular matrix or other cells. Ligand binding changes their conformation and causes clustering, allowing intracellular kinases and adaptor proteins to transmit signals.

How can mechanical forces serve as cellular signals?

Changes in matrix stiffness, tension, or cell attachment can be detected through integrins, focal adhesions, and the actin cytoskeleton. These mechanotransduction pathways can alter protein activity and gene expression, including through regulators such as YAP1.

MAPK/ERK pathway

The MAPK/ERK pathway is a phosphorylation cascade commonly organized as RAS $\rightarrow$ RAF $\rightarrow$ MEK $\rightarrow$ ERK. It transmits signals from receptors such as the EGF receptor to the nucleus and can regulate gene expression, translation, and cell division.

How does EGF signaling through ERK affect protein synthesis?

EGF receptor activation produces a phosphorylation cascade that activates ERK. Phosphorylated ERK enters the nucleus and activates MNK1, which phosphorylates eIF-4E; this promotes mRNA unfolding and initiation of protein synthesis.

What is protein kinase C (PKC) in the context of signal transduction?

PKC is a protein kinase that can phosphorylate signaling proteins and regulate processes such as transcription. In the NF-κB pathway, PKC phosphorylates and inactivates Iκ-B, indirectly activating NF-κB.

How can phosphorylation activate transcription by inhibiting an inhibitor?

PKC phosphorylates Iκ-B, an inhibitor bound to the transcription factor NF-κB. Phosphorylated Iκ-B can no longer retain NF-κB, allowing NF-κB to enter the nucleus and promote RNA transcription.

How does adrenaline increase the availability of glucose in muscle cells?

Adrenaline activates $\beta$-adrenergic GPCRs, increasing intracellular $cAMP$. $cAMP$ activates PKA, which promotes glycogen breakdown through glycogen phosphorylase and inhibits glycogen synthesis by phosphorylating glycogen synthase.

Describe the adrenaline pathway from receptor activation to glycogen breakdown.

Adrenaline $\rightarrow$ $\beta$-adrenergic receptor $\rightarrow$ increased $cAMP$ $\rightarrow$ PKA $\rightarrow$ glycogen phosphorylase kinase $\rightarrow$ glycogen phosphorylase $\rightarrow$ glycogen breakdown into glucose monomers.

Why does adrenaline signaling prevent a futile cycle in muscle cells?

PKA simultaneously activates enzymes that degrade glycogen and inhibits glycogen synthase, which would rebuild glycogen. Thus, the cell does not rapidly synthesize and degrade glycogen at the same time.

Growth factor

A growth factor is a ligand that promotes cell growth, survival, or division. Many growth factors act through receptor tyrosine kinases and downstream MAP kinase pathways.

How can cell signaling regulate cell division?

Growth factor binding activates receptors such as RTKs, which can activate RAS and the MAPK pathway. Downstream transcriptional changes produce proteins that interact with cell-cycle machinery and promote division.

What is constitutive receptor activation?

Constitutive activation occurs when a receptor signals continuously without ligand binding, often because of overexpression or mutation. Persistent activation of growth receptors such as HER2 can promote hyperproliferation and cancer.

Why can an overactive RAS protein promote cancer?

RAS normally acts as a regulated molecular switch downstream of growth-factor receptors. Mutant RAS may remain active without an appropriate signal, continuously stimulating pathways that promote cell growth and division.

What is an oncogene, and how can a signaling mutation cause cancer?

An oncogene is a gene with the potential to promote cancer when abnormally activated or expressed. A mutation that keeps a signaling protein, receptor, or growth pathway active can disrupt cell-cycle regulation, causing uncontrolled division, tumor formation, and possibly metastasis.

How can HER2 overexpression contribute to cancer, and how does trastuzumab target it?

Gene duplication or other changes can cause excessive HER2 receptor expression, increasing growth signaling and promoting uncontrolled proliferation. Trastuzumab is a monoclonal antibody that binds HER2 and helps the immune system remove HER2-expressing cells, reducing the signal.

Apoptosis

Apoptosis is programmed cell death carried out in a controlled manner. It removes damaged, unnecessary, infected, or potentially dangerous cells while limiting the release of harmful intracellular contents.

How does apoptosis differ from uncontrolled cell damage?

Apoptosis is an internally regulated process that safely dismantles a cell. In contrast, uncontrolled cell damage can cause cell contents to leak into surrounding tissue and trigger harmful inflammation.

What can initiate apoptosis?

Internal checkpoints can detect cellular abnormalities and activate apoptosis. External signals can also trigger it, such as loss of attachment to the extracellular matrix or recognition of self-reactivity during T-cell development.

Why does loss of extracellular-matrix attachment trigger apoptosis in many animal cells?

Binding to the extracellular matrix provides survival signals through cell-surface receptors. If a cell detaches, those signals stop, inducing apoptosis and helping prevent cells from migrating and proliferating in inappropriate locations.

How does apoptosis during T-cell development reduce autoimmune disease risk?

Immature T cells are tested for binding to self proteins. Cells whose receptors strongly recognize self undergo apoptosis, removing potentially dangerous cells before they can attack the organism's own tissues.

What developmental role does apoptosis play in forming separate fingers and toes?

Early embryonic limbs contain tissue between developing digits. Apoptosis removes these unnecessary cells, allowing the fingers and toes to become separated.

How can failure of apoptosis contribute to cancer?

If abnormal or excessively dividing cells evade programmed death, they can survive and continue proliferating. This failure, combined with excessive growth signaling, can promote tumor formation.

Why is terminating a signaling pathway as important as initiating it?

Persistent signaling can cause inappropriate gene expression, metabolism, growth, or survival. Proper termination ensures that the response is temporary and prevents pathological outcomes such as uncontrolled proliferation.

What are major mechanisms for terminating a ligand-mediated signal?

The ligand can be degraded or removed so it cannot bind its receptor, and receptors or downstream proteins can be inactivated. Intracellular second messengers can also be degraded or pumped back into storage compartments.

How do phosphatases and phosphodiesterases terminate signaling?

Phosphatases remove phosphate groups added by kinases, reversing protein phosphorylation. Phosphodiesterases hydrolyze $cAMP$ into AMP, lowering the concentration of this second messenger.

How is a signaling increase in cytoplasmic $Ca^{2+}$ reversed?

$Ca^{2+}$ pumps transport calcium out of the cytoplasm, either across the plasma membrane or back into intracellular storage compartments. This restores the low resting cytoplasmic calcium concentration.

How do signaling pathways form networks rather than isolated chains?

Pathways can share components, branch to multiple effectors, or feed back onto earlier steps. These interactions allow cells to integrate several signals and coordinate responses such as metabolism, growth, differentiation, and apoptosis.

What types of stimuli besides chemical ligands can activate signal transduction?

Cells can detect mechanical force, osmolarity, temperature, light, DNA damage, and other physical or intracellular conditions. Specialized receptors or sensors convert these stimuli into biochemical signals.