Cell Signaling and Cytoskeleton Mechanisms

Posted on Apr 17, 2026 in Health Biology

1. Signaling Big Picture

  • Cellular Response: Cells detect extracellular signals, measure ligand concentration, relay/amplify information, and trigger changes in enzyme activity, gene expression, secretion, cytoskeletal behavior, motility, survival, or cell-cycle progression.
  • Intercellular Modes: Contact-dependent (juxtacrine), paracrine, synaptic, and endocrine. Synaptic signaling is local, fast, and low-affinity; endocrine is long-range, dilute, and usually high-affinity.

2. Receptor Classes

  • Ion-Channel-Coupled: Directly alter membrane permeability; used for rapid synaptic signaling.
  • GPCRs: 7-pass transmembrane proteins signaling through heterotrimeric G proteins and second messengers (cAMP, IP3, DAG, Ca2+).
  • Enzyme-Coupled: Single-pass TM proteins with intrinsic or recruited enzyme activity (e.g., RTKs, JAK-associated cytokine receptors).
  • Nuclear Receptors: Intracellular receptors for small hydrophobic ligands that diffuse through the membrane to alter transcription.

3. Signal Termination

  • G Proteins: Terminated by GTP hydrolysis. GPCRs desensitize via GRK phosphorylation, arrestin binding, and internalization.
  • Second Messengers: Terminated by degradation (phosphodiesterases for cyclic nucleotides), removal (Ca2+ pumps), or reversal (phosphatases).
  • RTK Pathways: Terminated by phosphatases, receptor endocytosis, and GAPs for small GTPases.

4. GPCR Core Cycle

  • Activated GPCR acts as a GEF for Gα, triggering GDP to GTP exchange. Gα-GTP dissociates from Gβγ to signal to effectors.
  • Note: Heterotrimeric G proteins are distinct from small monomeric GTPases like Ras, Rho, Rab, Ran, and Arf.

5. Gs, Gi, and Gq Logic

  • Gs: Activates adenylyl cyclase → increases cAMP → activates PKA. PKA phosphorylates targets and CREB.
  • Gi: Inhibits adenylyl cyclase → lowers cAMP/PKA output.
  • Gq: Activates PLCβ → cleaves PIP2 into IP3 and DAG. IP3 triggers Ca2+ release; DAG and Ca2+ activate PKC.

6. Second Messengers and Domains

  • Messengers: cAMP, cGMP, DAG, IP3, Ca2+.
  • Domains: SH2/PTB (phosphotyrosines), SH3 (proline-rich), PH (phosphoinositides), EF-hand (Ca2+), RING (ubiquitin ligase).

7. Proteolysis-Dependent Signaling

  • Notch: Synthesized as a precursor, cleaved in the Golgi, and undergoes further cleavage upon Delta binding to release the cytosolic tail for nuclear translocation. Common in developmental cell-fate decisions.

8. RTK Activation and Ras/MAPK

  • Ligand binding promotes RTK dimerization and trans-autophosphorylation.
  • Pathway: Grb2 (SH2/SH3) recruits Sos (Ras GEF) → Ras-GTP → Raf (MAPKKK) → Mek (MAPKK) → Erk (MAPK).

9. PI3K/Akt Survival Pathway

  • RTKs recruit PI3K, converting PIP2 to PIP3. PIP3 recruits PDK1 and Akt via PH domains.
  • Regulation: PTEN converts PIP3 back to PIP2, antagonizing Akt-mediated survival.

10. JAK-STAT and TGFβ/Smad

  • JAK-STAT: Cytokine receptors recruit JAKs, which phosphorylate STATs; STATs dimerize and enter the nucleus.
  • TGFβ: Receptor Ser/Thr kinases; Type II activates Type I, which phosphorylates Smads.

11. Wnt/β-Catenin Signaling

  • Without Wnt: Destruction complex (Axin/APC/CK1/GSK3) phosphorylates β-catenin, leading to degradation.
  • With Wnt: Frizzled/LRP activation inhibits the destruction complex, allowing β-catenin to accumulate and activate TCF/LEF transcription.

12. Cytoskeleton Systems

  • Actin Filaments: Polar, dynamic, ~5–9 nm.
  • Microtubules (MTs): Polar, dynamic, ~25 nm.
  • Intermediate Filaments (IFs): Nonpolar, tensile strength, ~10 nm (e.g., lamins, keratins).

13. Actin Dynamics

  • Treadmilling: Occurs when the concentration of free monomers is between the critical concentrations (Cc) of the plus and minus ends.
  • Regulators: Thymosin (sequesters monomers), Profilin (promotes plus-end addition), Cofilin (promotes turnover of ADP-actin), Arp2/3 (branched networks), Formins (unbranched filaments).

14. Microtubule Essentials

  • Dynamics: GTP-cap stabilizes the growing end; loss of cap leads to catastrophe; regrowth leads to rescue.
  • Proteins: EB1 (tracks growing plus ends), XMAP215 (polymerase), Kinesin-13 (depolymerase).

15. Motor Proteins

  • Dynein: Minus-end directed.
  • Kinesin-1: Plus-end directed.
  • Myosin II: Low duty ratio, powers contraction.

16. Cell Cycle Control

  • Cdks: Activity regulated by cyclin levels, phosphorylation, and CKIs.
  • APC/C: E3 ligase that triggers the metaphase-anaphase transition by destroying securin and cyclins.
  • Checkpoints: Spindle assembly checkpoint (kinetochore attachment) and DNA-damage checkpoints ensure genomic integrity.