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Signal-Transduction Pathways

Chapter 13: Signal-Transduction Pathways Notes

These notes are for the personal, educational, and noncommercial use of students enrolled in BMB:3110 at the University of Iowa. Explanatory text and content were developed by Anneke Sanders © 2025. Illustrations are copyrighted material from Biochemistry, A Short Course, 5th Ed. By Hines, Reinke, Tymoczko, W.H. Freeman & Co, 2025.

Learning Objectives:

Upon completion of this material, you should be able to:

  • Describe the basic structure of a signal transduction pathway.
  • Compare different signaling pathways based on receptor types (7TM/GPCR, dimeric receptor kinases, dimeric receptors).
  • Understand how signals are received, amplified, transduced, and downregulated.
  • Grasp the role of second messengers.
  • Understand the involvement of G proteins and small GTPases in signal transduction and their regulation.
  • Know the example pathways discussed.
  • Understand how deregulation of pathways contributes to disease.

Signal Transduction: Molecular Circuits

Signal transduction relies on molecular circuits and follows a similar process across various pathways, encompassing five fundamental steps:

  1. Primary Messenger: A stimulus or trigger releases a signal molecule into the extracellular space.
  2. Reception of Primary Messenger: Receptors situated on the cell membrane or within the cell bind the primary messenger, thereby transferring information from the extracellular to the intracellular environment.
  3. Transduction and Amplification by Second Messengers:
    • Structural changes in the receptor, induced by ligand binding, lead to an increased local concentration of intracellular molecules known as second messengers.
    • Second messengers relay information from the receptor to downstream targets.
    • This step can also involve protein-protein interactions and protein modifications (e.g., phosphorylation).
    • Amplification is a key aspect, where a small initial signal generates a large intracellular response.
  4. Physiological Response: The final effectors (e.g., enzymes controlling metabolic pathways) are either activated or inhibited, resulting in a specific cellular response.
  5. Termination of Signaling: The signaling cascade must be promptly stopped after the information has been successfully transferred to prepare the system for new signals and prevent overstimulation.

Overview of Receptors and Transducers

Despite a multitude of specific molecules, signaling pathways utilize a limited set of receptor structures and mechanisms:

Receptor Proteins

These proteins bind extracellular molecules and transmit information across the cell membrane into the intracellular space.

  • 7 Transmembrane-Helix Receptors (7TM): Also known as G-protein coupled receptors (GPCRs), an example is the eta2-adrenergic receptor.
  • Dimeric Receptors that Recruit Kinases: These receptors dimerize upon ligand binding and then recruit separate kinase enzymes, such as the Growth Hormone (GH) receptor.
  • Dimeric Receptor Kinases: These receptors themselves possess kinase activity and dimerize upon ligand binding, leading to auto-phosphorylation and phosphorylation of downstream targets, exemplified by the epidermal growth factor receptor (EGFR).

Transducers

These molecules act downstream of receptors to either produce second messengers or affect protein-protein interactions, amplifying and relaying the signal.

  • Examples: Trimeric G-protein, adenylate cyclase, protein kinase A, phospholipase C, protein kinase C, Janus kinase (JAK), Grb-2, Sos, Ras (a monomeric G protein), IRS (Insulin Receptor Substrates), PI3K (PIP3 kinase), PDK1 (PIP3-dependent kinase), Akt kinase.
  • Transducers often operate in cascades, regulating and amplifying the initial signal.

7 Transmembrane-Helix Receptors (7TM / GPCRs)

  • Ubiquitous Receptors: These receptors are found throughout the body and are involved in a vast array of biological functions, mediating ext{50\%} of drugs currently in use.
  • Structure: Characterized by seven transmembrane ext{\alpha}-helices.
  • Signal Diversity: They receive a wide variety of signals, including hormones, odorants, neurotransmitters, and photons.
  • Mechanism: Ligand binding to the extracellular domain induces a conformational change in the cytoplasmic domain, activating an associated G-protein.
  • Example: The eta2-adrenergic receptor recognizes epinephrine (adrenaline) and activates the