Signaling Systems


Epidermal Growth Factor Receptor (RTK)

→ a receptor tyrosine kinase (enzyme-coupled receptor) that promotes cell growth, survival & repair, especially in epithelial tissues

  • kinase phosphorylates tyrosine by taking a phosphate group from ATP and attaching it, to speed up chemical reaction

  • extracellular signals → kinase cascades (really long chain)

  • STEPS

    • EGF (aka mitogen, which signals cell to begin mitosis) binds to EGFR (process called receptor dimerization, which pairs individual receptors)

    • autophosphorylation (each individual receptor’s kinase puts a phosphate on the other’s tyrosine)

    • Grb2 (“GF receptor bound protein 2”, an adapter protein) binds to the phosphates on the tyrosines

    • attached to Grb2 is SOS ("son of sevenless”, a GEF “guanine nucleotide exchange factor” which turns on a switch protein from inactive to active)

    • SOS activates RAS (“rat sarcoma protein”, a G-protein GTPase enzyme powered by GDP/GTP) by catalyzing GDP-GTP exchange (opens RAS up to drop GDP for GTP)

      • RAS + GDP = OFF

      • RAS + GTP = ON

    • RAS-GTP activates RAF (“rapidly accelerating fibrosarcoma kinase”, MAPKKK, phosphorylates serine/threonine) by having it phosphorylated by helper proteins/autophosphorylation

    • RAF activates MEK (“mitogen activated protein kinase kinase”, MAPKK, a dual specificity kinase which phosphorylates both threonine and tyrosine) by phosphorylating its serines

    • MEK activates ERK (“extracellular signal regulated kinase”, a MAP kinase* with threonine & tyrosine) by phosphorylating its threonine & tyrosine

    • ERK enters nucleus and activates transcription, cell cycle entry & inhibition of apoptosis

*mitogen-activated protein

  • Scaffold/Platform - EGFR → Grb2 → SOS

  • Relay Switch - RAS-GTP/GDP

  • Relay Amplification System - MAPK pathway (RAF, MEK, ERK*)

*also a terminal effector


Glucagon Receptor (GPCR)

→ a g-protein-coupled receptor that regulates blood glucose levels during fasting (Gs-coupled)

  • STEPS

    • glucagon (hormone) binds to GCGR on liver cell surface

    • GCGR activates heterotrimeric G-protein (like a GEF; turns on a switch protein from inactive to active) by promoting GDP-GTP exchange on Gas subunit (a GTPase powered by GDP-GTP; which breaks off from beta and gamma subunit after picking up GTP)

    • Gas-GTP activates adenylyl cyclase (enzyme; chemical converter)

    • adenylyl cyclase converts ATP → cAMP (second messenger; amplifier)

    • lots of cAMP activates PKA (“protein kinase A”; terminal effector; phosphorylates serine/threonine on metabolic enzymes & transcription factors involved in glucose release)

  • receptor & g-protein resets after GTP → GDP (GTP hydrolysis) + reassociation

  • Relay Amplification System - cAMP/PKA pathway


a1-Andrenergic Receptor (GPCR)

→ a g-protein coupled receptor that responds to adrenaline (epinephrine), triggering smooth muscle contraction (vasoconstriction)

  • uses a Gq-coupled GPCR pathway, generating two second messengers: IP3 & DAG

  • demonstrates signal branching & compartmentalization

  • STEPS

    • adrenaline binds to a1-andrenergic receptor

    • receptor activates Gq protein (GTP-GTP exchange on Gaq; a GTPase which breaks off from beta and gamma subunit after picking up GTP)

    • Gaq-GTP activates PLCB (“phospholipase C-B”; lipid-cleaving enzyme)

    • PLCB cleaves PIP2 (membrane phospholipid) → IP3 (“inositol triphosphate”; which releases Ca2+ from endoplasmic reticulum) & DAG (“diacylglycerol”; stays in membrane; activates PKC “protein kinase C”)

      • Ca2+ activates calmodulin (enzyme regulator)

    • Second Messengers (amps) - IP3 & DAG

    • Downstream Effectors - Ca2+, calmodulin & PKC


Nicotinic Acetylcholine Receptor (Ligand-Gated Ion Channel)

→ a ligand-gated ion channel receptor essential for signaling at the neuromuscular junction and many other regions of the CNS

  • enables fast synaptic transmission by allowing ion flow across membrane in response to acetylcholine

  • electrical signal with direct transduction (non-amplified, immediate signaling)

  • STEPS

    • ACh (“acetylcholine”; ligand) released into synaptic cleft, binding to the nAchR (“nicotinic acetylcholine receptor”; a pentameric channel protein)

    • channel opens → Na+ & K+ ions flow across membrane

    • depolarization (cell’s electrical charge inside is more positive) triggers action potential (or muscle contraction)


Erythropoietin Receptor (Cytokine Receptor)

→ regulates RBC production (on erythroid progenitor cells) in response to O2 levels

  • no intrinsic enzyme activity; recruits cytoplasmic kinases instead

  • reversible via phosphatases or proteasomal degradation of signaling proteins

  • STEPS

    • Epo (“erythropoietin”; hormone/ligand) binds to EpoR resulting in receptor dimerization (which pairs individual receptors)

    • JAK2 kinases (“janus kinase 2”; cytoplasmic tyrosine kinase) attached at the ends of the receptor cross-phosphorylate each other

    • phospho-tyrosines on EpoR recruit STAT5 (“signal transducer and activator of transcription 5”; a free floating transcription factor) phosphorylating it which makes STAT5 let go of the receptor and bind to another STAT5 molecule (dimerization)

    • STAT5 dimers translocate to nucleus, activating transcription