Signal Transduction and Cell Regulation Notes

Signal Transduction Overview

• General Features: Signal transduction involves communication between and within cells, using various receptors and pathways.

• Major Types of Receptors:

  • G-protein coupled receptors (GPCRs)

  • Enzyme-linked receptors (e.g., Receptor Tyrosine Kinases)

  • Gated ion channels

  • Nuclear hormone signaling

• Importance of understanding connection between signaling and cell division.

Receptor Tyrosine Kinases (RTKs)

• Plasma membrane receptors with intrinsic tyrosine kinase activity.

• Composed of:

  • Extracellular ligand binding domain

  • Intracellular tyrosine kinase domain

• Function by activating cascades of protein kinases to relay metabolic information, often in response to growth factors.

Structure Details of RTKs

• Comprise intramolecular domains such as:

  • IgG-like domain

  • Cysteine-rich domain

  • Ligand-binding domain

  • Tyrosine kinase domain

• Common examples: INS-R (Insulin receptor), VEGF-R (Vascular Endothelial Growth Factor receptor), etc.

Autophosphorylation Mechanism

• Activation occurs via autophosphorylation:

  • Each beta subunit phosphorylates three critical tyrosine residues on another subunit’s C-terminus, thereby opening the active site.

Gene Expression Regulation by Insulin

• Insulin receptor substrate 1 (IRS1) becomes a recruitment point for various proteins transferring signals downstream.

• SH2 domain: Binds specifically to phosphorylated tyrosine residues on target proteins.

MAPK Pathway Components

• Raf-1, MEK, ERK are key components in the MAPK cascade:

  • ERK: Specific for serine/threonine residues.

  • MEK: Phosphorylates both serine and tyrosine residues.

  • Raf-1: A MAP kinase kinase kinase activating MAPK.

PIP3 Signaling in Insulin Pathway

• PIP3 derived from the conversion of PIP2 by PI3K, initiated by activated IRS1, facilitates GLUT4 translocation to the plasma membrane and stimulates glycogen synthesis.

Insulin Signaling Termination

• Mechanisms for signal termination include:

  • Decrease of insulin levels below receptor Kd.

  • Ras GTPase activity.

  • PTEN phosphatase converting PIP3 back to PIP2.

Interconnection of Signaling Systems

• Extensive connections among signaling pathways allow for integration and optimization of hormonal responses.

Ion Channels for Electrical Signaling

• Ion channels play crucial roles in electrical transmission within neurons.

• They can be voltage-gated (triggered by membrane potential changes) or ligand-gated (activated by specific ligand binding).

• The transient opening of these channels influences membrane potential and facilitates rapid signaling.

Voltage-Gated Ion Channels

• Na+ and K+ channels propagate action potentials by mediating:

  • Depolarization (Na+ influx)

  • Repolarization (K+ efflux)

• The progression of an action potential travels along the axon and triggers neurotransmitter release at the synapse.

Structure of Neuronal Sodium Channels

• Comprised of four homologous domains, each with six transmembrane helices, essential for channel function:

  • Helix 4: Voltage sensor.

  • Helix 6: Activation gate.

  • Inactivation gate between domains III and IV that responds to changes in membrane potential.

Neurotoxins and Ion Channels

• Neurotoxins can selectively target ion channels, impairing neural signaling:

  • Dendrotoxin (affects K+ channels)

  • Tetrodotoxin (affects Na+ channels)

  • Cobrotoxin (affects acetylcholine receptors).

Steroid Hormones and Gene Expression

• Steroid hormones can cross the cell membrane and bind to specific receptor proteins, influencing gene expression by interacting with hormone response elements (HREs) in DNA.

Connection Between Signaling and Cancer

• Cell signaling is crucial for proper cell cycle regulation; any defects can lead to tumor development.

• Oncogenes: Mutated versions of genes that promote cell division; genetically dominant.

• Tumor suppressor genes: Encode proteins that inhibit cell division; mutations are typically recessive, requiring both alleles to be defective for tumorigenesis to occur.

Cell Cycle Control and Regulation

• The cell cycle consists of different phases: primarily M phase, G1, G0 (resting phase), etc.

• Cyclin-dependent kinases (CDKs) regulate the timing of the cell cycle, requiring binding to cyclins.

Growth Factors and Cell Division

• Growth factors stimulate cell division by activating transcription factors through phosphorylation of CDK regulators.

• Specific inhibitors can also modulate CDK activity, presenting potential cancer treatments.