Cell Signaling I - Principles of Cell Signaling

Cell Signaling I - Principles of Cell Signaling

• Lecture date: 11/4/2024
• Instructor: Tobias Weinrich, PhD
• Institution: The University of Texas Rio Grande Valley

Student Learning Outcomes

• Describe the main ways cells signal.
• Explain the three phases of a general signaling cascade.
• Identify and describe the different types of molecules involved in signaling pathways.
• Relate receptor location to the type of signaling molecule.
• Differentiate between specificity, amplification, adaptation, integration, and signal distribution steps in a signaling cascade.
• Explain different types of response times to extracellular ligands.
• Identify mechanisms for deactivating signaling pathways.
• Correctly interpret schematic representations of signaling cascades.

Lecture Structure

• Types of Cell Signaling
• Stages of Cell Signaling
• Types of signaling molecules
  • Extracellular signaling molecule (ligand)
  • Receptor proteins
  • Intracellular signaling proteins (enzymes, molecular switches, second messengers)
  • Effector proteins
• Signal transduction

Types of Cell Signaling

1. Direct Cell-Cell Contact (Juxtacrine):
   • Membrane-bound signaling molecule.
   • Does not involve secreted molecules.
2. Signaling by Secreted Molecules:
   • Endocrine (long distance, bloodstream) - hormones
   • Paracrine (neighboring cells) - local mediators
   • Neuronal (synaptic) - neurotransmitters
   • Autocrine (signaling cell is the target)

Stages of Cell Signaling

1. Signal reception: ligand and receptor interaction
2. Signal transduction: interpretation of the signal
3. Cellular response: altered metabolism, altered cell shape, altered gene expression

Types of Molecules

• Ligand (primary messenger): extracellular signaling molecule
• Receptor protein: cell surface, intracellular
• Proteins (enzymes)
• Non-proteins (second messenger)
• Effector/target proteins (Metabolic Enzyme, Transcription Factor, Cytoskeletal Protein)

Signal Molecules (Primary Messengers)

• Extracellular signal molecules: hormones, photons, mechanical force, chemical odorants, membrane-bound signaling molecules, macromolecules (proteins, lipids, carbohydrates, nucleic acids), neurotransmitters
• Epinephrine, cortisol, estradiol, testosterone, thyroid hormone, insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), histamine, nitric oxide (NO), acetylcholine, etc.

Receptor Proteins

1. Intracellular: hydrophobic ligands
   • Enzyme (example: NO receptor, guanylyl cyclase)
   • Transcription factors (nuclear receptors)
2. Cell surface: hydrophilic ligands
   • Ion channel-coupled receptors
   • G-protein-coupled receptors
   • Enzyme-coupled receptors
   • Intrinsic enzymatic activity and associated enzymatic activity

Intracellular Signaling Molecules (Enzymes)

• Kinases (PKA, PKC, receptors, tyrosine, serine/threonine phosphatases)
• Monomeric G proteins (small G proteins, GTPases)
• Adenylyl cyclase (convert ATP to cyclic AMP, cAMP)
• Guanylyl cyclase (convert GTP to cyclic GMP, cGMP)
• Phospholipases (cleave phospholipids in the cell membrane)
• Proteases (precursor proteins to active proteins, example: pro-caspases to caspases)

Intracellular Signaling Molecules (Second Messengers)

• Small, non-protein, intracellular molecules
• Short half-life
• Relay and amplify first messenger (ligand) signal
• Pass info. to other signaling proteins (cyclic AMP, cAMP, DAG, IP3, Ca2+)

Signal Transduction

• Interaction of a receptor and ligand causing behavioral changes in the cell (or changes to gene expression).
• Relay, amplification, integration, distribution.

Specificity

• Signaling molecules bind receptors on target cells
• Same ligand can induce different responses in the target cell (based on receptor type).
• Different receptors lead to diverse responses.

Integration and Coordination

• Multiple signaling pathways in a cell interact to enable the cell to respond to a mixture of external signals.
• Responses depend on signaling molecule number and strength.
• In the absence of appropriate signals, the cell may die (apoptosis).

Dynamics - Speed

• Fast responses result from impacting existing proteins (activation/inhibition) and/or ion channel changes.
• Slow responses involve gene expression changes.
• Duration of ligand presence/exposure can affect cell behavior

Dynamics - Deactivation of Signaling Pathways

• Receptor sequestration (receptor endocytosis)
• Receptor down-regulation (receptor endocytosis and digestion)
• Receptor inactivation
• Phosphorylation of receptor
• Inactivation or proteolysis of signaling molecule
• Production of inhibitory protein

Dynamics - Sensitivity, Adaptation and Amplification

• Sensitivity: Receptors detect very small ligand amounts resulting in changes to cell behavior. This sensitivity is achieved by signal amplification.
• Adaptation: Signal pathways adapt to the ligand amount, letting the cell respond to minor changes in the ligand concentration.

Dynamics - Optimization

• Scaffold proteins: Organize the complex of signaling molecules.
• Membrane domains: Lipid rafts (specific lipid clusters)
• Phosphoinositides: Membrane domains containing these phospholipids anchor and recruit signaling molecules.
• Activated receptor: Recruitment of signaling proteins