Cell Signaling Systems

What is a cell signaling pathway?

A linked set of biochemical reactions initiated by ligand-induced activation of a receptor leading to a measurable cellular response.

What is signal transduction?

The biochemical mechanism for transmitting extracellular signals across the plasma membrane and throughout the cell.

What is a first messenger?

A ligand that binds to a receptor protein, triggering a cellular response.

What is a second messenger?

Small molecules used to amplify the signal in a signaling pathway.

What are common outcomes of signaling pathways?

Gene expression, cell mobility, ion channel activity, and metabolic flux.

What are the five classes of receptor proteins in eukaryotes?

G protein-coupled receptors, receptor tyrosine kinases, tumor necrosis factor receptors, nuclear receptors, and ligand-gated ion channels.

What activates a G-protein coupled receptor (GPCR)?

Ligand-induced conformational change.

What are the structural features of GPCRs?

Integral membrane protein with 7 transmembrane helices, extracellular N-terminus, intracellular C-terminus.

What happens when GPCRs are activated?

GDP is replaced by GTP on the G-protein, leading to dissociation of the heterotrimeric complex into Gα and Gβγ subunits.

What is the role of adenylate cyclase in GPCR signaling?

Converts ATP to cAMP, which activates Protein Kinase A (PKA).

What is the function of PKA?

Phosphorylates Ser and Thr residues on target proteins to regulate metabolic pathways.

What is the result of glucagon binding its receptor on liver cells?

Stimulation of Gsα, activation of AC, increase in cAMP, and activation of PKA leading to glycogen degradation.

What do DAG and IP3 do in the phosphoinositol cascade?

DAG activates PKC, and IP3 increases intracellular Ca²⁺ by opening ER channels.

What is the role of calmodulin in signaling?

Binds Ca²⁺ and activates various target proteins.

What enzyme converts PIP2 to DAG and IP3?

Phospholipase C (PLC).

What is the function of a GEF (guanine nucleotide exchange factor)?

Activates signaling by promoting GDP-GTP exchange on G proteins.

What is the function of a GAP (GTPase activating protein)?

Inhibits signaling by stimulating GTP hydrolysis on G proteins.

How are GPCRs deactivated?

Phosphorylation by β-ARK and binding of β-arrestin, followed by endocytosis.

What activates receptor tyrosine kinases (RTKs)?

Ligand binding and dimerization of the receptor.

What is the role of autophosphorylation in RTK signaling?

Creates docking sites for adaptor proteins like GRB2 and SOS.

What is Ras?

A lipid-anchored G-protein activated by SOS that initiates the MAPK pathway.

What are the three key proteins in the MAPK pathway?

Raf, MEK, and ERK.

What is a proto-oncogene?

A normal gene that can become an oncogene due to mutations.

What is a tumor suppressor gene?

A gene that inhibits cell growth

What causes constitutive activation of Ras in cancers?

Mutations that decrease its GTPase activity or GAP binding.

What is the structure of the insulin receptor?

A disulfide-linked αβ dimer, permanently dimerized, with α binding insulin and β having kinase activity.

What does insulin binding lead to?

Autophosphorylation of β subunit, activation of IRS proteins, and PI3K pathway activation.

What is the role of PI3K?

Converts PIP2 to PIP3, activating PDK1 and Akt, promoting glucose uptake and cell survival.

What terminates PI3K signaling?

PTEN, which converts PIP3 back to PIP2.

What are TNF receptors?

Trimeric receptors with intracellular death domains that mediate survival or apoptosis depending on adaptor binding.

What happens in the apoptotic TNF pathway?

TRADD recruits FADD, which activates CASP8 and CASP3 to induce cell death.

What does TRAF2 do in TNF signaling?

Promotes cell survival by activating NF-κB through NIK and RIP kinases.

What is the function of nuclear receptors?

Intracellular receptors that act as transcription factors when bound to lipophilic ligands.

How do nuclear receptors bind DNA?

As dimers, either homodimers or heterodimers, to specific DNA repeat sequences.

What is a GRE (glucocorticoid response element)?

A DNA sequence in gene promoters bound by glucocorticoid receptors to regulate gene expression.

What is the role of heat shock proteins (Hsps) in nuclear receptor signaling?

Stabilize unliganded receptors and dissociate upon ligand binding.

What is the glucocorticoid receptor involved in?

Lung development, carbohydrate metabolism, inflammation, and neuronal signaling.

What does dexamethasone do?

Mimics cortisol to reduce inflammation and is used in severe COVID-19.

What is the biological role of GPCRs?

Sensory perceptions such as taste, vision, smell, and general perception including emotions.

What is the conserved motif in GPCR activation?

The DRY motif, which breaks an ionic lock upon ligand binding.

What are agonists in GPCR signaling?

Molecules that activate the receptor by mimicking the natural ligand.

What are antagonists in GPCR signaling?

Molecules that bind with high affinity to block agonist binding and inhibit signal transduction.

What are the types of Gα subunits and their effects?

Gs (increases cAMP), Gi (decreases cAMP), Gq (activates PLC), Gt (affects cGMP PDE activity), Gz (neuronal).

What is the mechanism of G protein activation?

Ligand-bound GPCR induces GDP-GTP exchange, leading to dissociation into Gα and Gβγ.

What does PKA activation require?

Binding of cAMP to the regulatory subunits, leading to dissociation of the catalytic subunits.

What is the pseudo-substrate sequence in PKA regulation?

Arg-Arg-Gly-Ala-Ile, which mimics the substrate but cannot be phosphorylated.

What happens when α1-adrenergic receptor is stimulated in liver cells?

Activates Gqα, increases IP3 and DAG, and triggers the phosphoinositol cascade.

What is the function of Rac in signaling?

A G protein that activates PLC via its Switch II region and PH domain.

What domain allows proteins to bind PIP2/PIP3?

Pleckstrin Homology (PH) domain.

What enzymes regulate the duration of cAMP signaling?

Adenylate cyclase (AC) and cAMP phosphodiesterase (PDE).

How are GPCRs recycled?

Via endocytosis, dephosphorylation, and either degradation or return to the plasma membrane.

What is the role of β-arrestin in GPCR regulation?

Binds phosphorylated GPCRs and promotes endocytosis.

What activates the EGFR1 tyrosine kinase?

Binding of two EGF molecules leading to dimerization and autophosphorylation.

What adaptor proteins are involved in EGF signaling?

GRB2 and SOS.

What domains are present in GRB2?

One SH2 domain and two SH3 domains.

What does SOS do in EGF signaling?

Acts as a GEF for Ras, promoting GDP-GTP exchange.

What is the function of ERK in the MAPK pathway?

Dimerizes, translocates to the nucleus, and alters gene transcription to increase cell division.

What virus helped discover the Src kinase?

Rous sarcoma virus.

What kind of kinase is Raf?

A MAPKKK that activates MEK in the MAPK pathway.

What happens when Ras is mutated in cancer?

It can become constitutively active, continuously sending growth signals.

What subunits form the insulin receptor?

Two α and two β subunits, linked by disulfide bonds.

What domains are found in the β subunit of the insulin receptor?

Four structural domains including a tyrosine kinase domain.

What sites are autophosphorylated on the insulin receptor?

pY1158, pY1162, and pY1163.

What do IRS1 and IRS2 do?

Act as adaptor proteins

What does Shc activate in insulin signaling?

MAPK pathway for cell division.

What does IRS activate in insulin signaling?

PI3K pathway for glucose uptake and glycogen synthesis.

What enzyme converts PIP2 to PIP3?

PI3K.

What activates PDK1?

Binding to PIP3.

What activates Akt?

Phosphorylation by PDK1 and binding to PIP3.

What are the downstream effects of Akt activation?

Increased GLUT4 translocation and activation of glycogen synthase.

What terminates the PI3K pathway?

PTEN, which dephosphorylates PIP3 to PIP2.

How does PI3K promote cell survival?

By activating Akt and downstream anti-apoptotic proteins.

What are the two outcomes of TNF receptor signaling?

Cell survival or apoptosis.

What does TNF-α bind to?

Trimeric TNF receptors containing intracellular death domains.

What adaptor binds the TNF receptor's death domain?

TRADD.

What complex forms to initiate apoptosis?

TRADD-FADD-procaspase 8 complex.

What does caspase 8 activate?

Caspase 3, the executioner caspase.

What is the function of caspases?

Cysteine proteases that cleave at aspartate residues in target proteins.

What motif does caspase 8 recognize?

IETD (residues 172–175).

What is the role of TRAF2 in TNF signaling?

Activates the survival pathway via NFκB.

How is NFκB activated?

NIK and RIP phosphorylate IKK, which then activates NFκB.

What determines whether a TNF signal causes survival or death?

The relative concentrations of TRAF2+RIP versus FADD+procaspase 8.

What kind of ligands do nuclear receptors bind?

Lipophilic ligands such as steroid hormones, vitamins, and fatty acid derivatives.

What determines nuclear receptor activity?

Ligand binding, coactivator/corepressor recruitment, and chromatin accessibility.

What DNA motifs do steroid receptors target?

Inverted repeat sequences.

What DNA motifs do metabolite receptors target?

Direct repeat sequences.

What structural motif do nuclear receptors use to bind DNA?

Zinc finger domain.

What holds the zinc in the zinc finger?

Cysteine residues.

What is PPARγ?

A nuclear receptor that forms a heterodimer and binds direct DNA repeats

What is the function of LXXLL peptides?

Mimic the steroid receptor coactivator sequence for interaction with nuclear receptors.

What is the role of Hsp90 in nuclear receptor signaling?

Stabilizes unliganded receptors until ligand binding causes release.

What triggers glucocorticoid production?

Low blood sugar and stress.

What are glucocorticoid receptor functions?

Regulate lung development, inflammation, liver metabolism, and neural responses.

How do glucocorticoids suppress inflammation?

They promote annexin I expression and inhibit NFκB and COX-2 expression.