Receptors and Cell Signaling - Quick Reference Notes

Signals are emitted, received by receptors, and transduced into intracellular signaling that alters cell behavior
Activation of receptors triggers intracellular pathways that regulate effector proteins
Intracellular signaling varies by cell type; same signal can have different effects depending on the intracellular milieu
Morphogen gradients and trophic factors govern development and cell survival

Cell specialization: expression of receptors and signaling components changes during growth/division
Combinations of signals elicit different responses; diverse outcomes from a limited set of signals
Trophic factors are required for survival; absence can trigger programmed cell death
Morphogen gradients yield position-dependent fates; signaling centers determine outcomes

Direct signaling: cell-cell or cell-matrix interactions; contact-dependent; gap junctions allow passage of ions/water (not macromolecules)
Endocrine: signals act at distant sites
Paracrine: signals act on nearby cells
Autocrine: signals act on the secreting cell
Synaptic: neurons release signals into synaptic cleft
Signaling networks: positive and negative feedback; crosstalk between pathways

Steroids: hydrophobic, cross cell membrane; nuclear receptor superfamily; often dimerize and act as transcription factors
Nitric Oxide (NO): small, diffuses locally; NO synthase makes NO from arginine; activates guanylyl cyclase to produce $cGMP$ ; short range due to rapid decay
NO effectors: guanylyl cyclase activation; thiol nitrosylation

Peptide hormones: diverse, often distant-acting; 2–100s of aa
Neuropeptides: neurotransmitters or hormone-like signals
Growth factors: promote growth, division, differentiation
Neurotransmitters: act on postsynaptic receptors; transient signaling
Eicosanoids: local mediators from arachidonate; short half-life; regulate inflammation and clotting; synthesis involves PLA2 and COX enzymes
Receptors include ligand-gated ion channels and G-protein coupled receptors (GPCRs)

Ion-channel-coupled (ionotropic) receptors: rapid signaling; ligands open/close ion channels
GPCRs (7 transmembrane): heterotrimeric G proteins (Gs, Gi, Gq)
Enzyme-coupled receptors: mainly kinases (protein kinases) or kinase-associated receptors
Tyrosine Kinase Receptors (RTKs): intracellular tyrosine kinase domain; dimerization and transphosphorylation
Tyrosine-kinase-associated receptors: signal via cytoplasmic tyrosine kinases (e.g., JAKs)
Cytokine receptors: often signal via Jak/STAT
Receptor guanylyl cyclases: produce $cGMP$ upon ligand binding
Receptor serine/threonine kinases: TGF-β family; Smad signaling
Notable single-pass/multi-pass sensors: Notch, Frizzled/Wnt, Hedgehog, Patched, Death Receptors, Integrins

Resting state: α subunit bound to GDP; αβγ and receptor form a complex
Activation: ligand binding promotes GDP → GTP exchange; α dissociates from βγ; both act on targets
Deactivation: GTP hydrolysis by GTPase-activating proteins (GAPs) returns GDP-bound state
Major routes:
- Gs: activates adenylyl cyclase → $cAMP$ → PKA
- Gi: inhibits adenylyl cyclase
- Gq: activates PKC via DAG and increases Ca²⁺ via IP3
Note: βγ subunits also modulate effectors
Critical concepts: rapid, amplified responses; diverse effector targets

RTKs: ligand-induced dimerization; cross-phosphorylation; SH2-domain-containing proteins bind phosphotyrosines
Tyrosine-kinase-associated receptors: signal through cytoplasmic tyrosine kinases (e.g., JAKs) and STATs
Protein Tyrosine Phosphatases: terminate signaling by dephosphorylating phosphotyrosines
Receptor guanylyl cyclases: generate $cGMP$ ; modulate kinases and PDEs
Receptor serine/threonine kinases (TGF-β family): activate Smads
Activation via dimerization and transphosphorylation propagates signals to downstream pathways

Notch: Delta ligand binding triggers proteolytic cleavage; intracellular domain enters nucleus as transcription factor
Frizzled (Wnt): modulates β-catenin; in the active state, β-catenin accumulates and drives transcription with TCF/LEF
Hedgehog: Patched/Moore complex controls Smoothened; Ci transcription factor is regulated; target gene expression
Death receptors: extrinsic apoptosis; ligands include cytokines; involve death domains and adaptor proteins

Integrins bind ECM; organized into focal adhesions and hemidesmosomes
Focal Adhesion Kinases (FAKs) link integrins to signaling networks
Activation promotes proliferation, survival, and gene expression via downstream pathways

$cAMP$ : synthesized by adenylyl cyclase; degraded by $cAMP$ phosphodiesterase; activates Protein Kinase A (PKA)
$cGMP$ : synthesized by guanylyl cyclase; degraded by phosphodiesterases; activates kinases, ion channels, and phosphodiesterases
$PIP2$ : membrane lipid cleaved by Phospholipase C (PLC) to generate $IP3$ and $DAG$
$IP3$ : releases Ca²⁺ from ER; activates Ca²⁺-dependent processes
$DAG$ : activates Protein Kinase C (PKC)
$PIP3$ : produced by PI3-kinase; activates Akt (a key survival and growth kinase)

Growth factor receptors activate Ras when bound by GEFs; Ras-GTP triggers a kinase cascade: $Ras{-}GTP <br /> ightarrow Raf <br /> ightarrow MEK <br /> ightarrow ERK$
ERK phosphorylates transcription factors to drive gene expression and cell fate decisions

Cytokine receptors recruit and activate JAKs
JAKs phosphorylate STATs; STATs dimerize and translocate to the nucleus to regulate transcription

TGF-β binds serine/threonine kinase receptors; phosphorylates Smad2/3
Smads form complexes with Smad4 and translocate to the nucleus to regulate transcription

Resting: NF-κB bound by IkB in the cytosol
Activation: IκB kinase (IKK) phosphorylates IkB; IkB is degraded; NF-κB enters nucleus to regulate target genes

Rho family GTPases regulate cytoskeleton: filopodia, lamellipodia, stress fibers
Activated by Integrins or growth factor receptors
Promote actin polymerization and coordinated cytoskeletal remodeling; modulate myosin activity