General Principles of Signaling Pathways

General Principles of Signaling Pathways

• Binding Sites: Specific regions on receptors where ligands attach; their structure affects ligand affinity and, consequently, signaling efficacy.
• Ligands: Molecules (e.g., hormones) that bind to receptors to initiate signaling; changes in their concentration or structure can disrupt signaling.
• Receptor Activation: Ligand binding induces receptors to change shape, activating downstream pathways; faulty activation can contribute to diseases like diabetes or cancer.
• Conformational Flexibility: The ability of receptors to adapt their shape for optimal ligand interaction; rigidity can impair function, while excess flexibility may cause inappropriate activation.
• Cooperativity: The phenomenon where the binding of one ligand influences the binding of additional ligands; loss of cooperativity can reduce signaling efficiency requiring higher ligand concentrations.
• Regulation: Involves feedback mechanisms with inhibitors and activators that maintain signaling levels; concentration, specificity, and reversibility are crucial for proper function.
• Reversibility: The capacity of signaling processes to reset after activation; important for maintaining homeostasis.
• Propagation/Amplification: Signaling pathways often amplify responses; effects of alterations can lead to exaggerated or diminished cellular responses.
• Termination and Reset: Mechanisms to deactivate signaling pathways; failure to terminate can result in persistent signaling and disease.

Specific Concepts in Signaling

• Mitogen: A substance that stimulates mitosis; examples include growth factors like EGF and signaling proteins like Ras.
• Dimerization: Two receptor molecules pair up due to ligand binding, essential for signal activation.
• Autophosphorylation: Receptors add phosphate groups to themselves, key for activating signaling cascades.
• SRC-Homology Domain (SH Domain): Protein domains (SH2 and SH3) facilitate signal transduction by binding phosphorylated tyrosines and promoting protein interactions.
• Growth Factor: Signaling molecules like EGF and NGF that stimulate growth and differentiation.
• Quorum Sensing: A bacterial communication process based on signaling molecule detection to coordinate group behaviors.
• Growth: Increase in cell size or number, regulated by signaling pathways.
• Development: Process of cell and tissue specialization involving mitosis and differentiation.
• Totipotency: A characteristic of zygotes allowing them to develop into any cell type in an organism.

MAPK Pathway and Key Mediators

• Key Mediators: Ras, RAF, MEK, ERK, which regulate cell proliferation.
• Consequences of Alterations:
  • Overactive Ras leads to uncontrolled ERK activation and cancer.
  • Inhibition of MEK results in impaired proliferative signals.

EGFR Signaling

• Key Mediators: EGFR, Grb2, Ras, PI3K, STAT proteins.
• Consequences of Alterations:
  • EGFR overexpression causes excessive proliferation.
  • Loss of Grb2 or STAT function reduces signaling and growth.

Integrin Signaling

• Key Mediators: FAK, Src, PI3K, Rho.
• Consequences of Alterations:
  • Loss of FAK affects cell migration.
  • Overactive Rho can disrupt normal cell movement.

Fas/Apoptosis Signaling

• Key Mediators: Fas receptor, FADD, caspases.
• Consequences of Alterations:
  • Inhibition of caspases prevents apoptosis, allowing unwanted cell survival.
  • Excess Fas activation may cause unwanted cell death.

NOTCH Signaling

• Key Mediators: NOTCH receptor, NICD.
• Consequences of Alterations:
  • Overactive NOTCH affects cell fate decisions, potentially leading to cancer.

Wnt Signaling

• Key Mediators: Wnt ligands, Frizzled receptor, β-catenin.
• Consequences of Alterations:
  • Loss of APC results in unregulated β-catenin activity, linked to colorectal cancer.
  • Deficient Wnt signaling impairs tissue development.

Tyrosine Kinase Receptor Activation Steps

• Ligand Binding: Initiates receptor dimerization.
• Dimerization: Essential for receptor activation; mutations can lead to various cancers.

Comparing Signaling Changes in Embryogenesis and Adults

• Embryogenesis: Critical for cell fate and differentiation; alterations can lead to congenital abnormalities or developmental malformations.
• Adults: Signaling changes affect tissue homeostasis and regeneration; can contribute to diseases like cancer or degenerative conditions.