Recording-2025-04-04T14:03:22.878Z

Signal Transduction and RAS Pathway

• Phosphorylation and Adapter Molecules

  • Hyperphosphorylation leads to the binding of adapter molecules to initiate the signal transduction cascade.

  • SOS (Son of Sevenless) is primarily involved in the RAS pathway.

• RAS Activation

  • RAS is received in an inactive GDP (Guanosine Diphosphate) form.

  • Activation occurs when a kinase receptor recruits RAS GAP (GTPase-Activating Protein), removing GDP and replacing it with GTP (Guanosine Triphosphate).

  • Active RAS interacts with various downstream proteins to propagate the signal.

• Cell Division Trigger

  • The RAS pathway is crucial in triggering cell division, involving extensive changes in protein activity.

  • Transitioning from G1 (Gap 1) to S phase (Synthesis) requires synthesizing machinery for DNA replication.

Kinase Cascade Amplification

• Kinase Cascade Mechanism

  • Kinases exist in phosphorylated (activated) and unphosphorylated (inactive) forms.

  • A MAP kinase is activated by a MAP kinase kinase, which is activated in turn by a MAP kinase kinase kinase (also referred to as MAP3K).

  • This amplification process allows for significant increases in output signals, with each kinase activating multiple downstream kinases.

• Importance of Amplification

  • Activation of a single MAP kinase kinase can lead to the activation of multiple MAP kinases, facilitating rapid cell signaling leading to cell division and other outcomes.

Activation and Inactivation Mechanisms

• Activation Process

  • Key activators include the RAS GTP form which activates the MAP kinase cascade.

  • Transcription factors are activated to promote gene expression for cellular changes.

• Inactivation Process

  • Every active component in signaling pathways has a corresponding inactivation mechanism.

  • For example, tyrosine kinase receptors can be inactivated by phosphatases, which remove phosphate groups, reverting the receptors to an inactive state.

RAS Protein and Cancer Links

• Mutation Impact

  • Mutations in the RAS gene are among the most common in cancer cells, leading to continuous activation of RAS even in the absence of signals.

  • Cancer-promoting mutations interfere with RAS's ability to interact with its inactivating GAP protein, keeping it constantly active.

Nuclear Receptors Overview

• Nuclear Hormone Receptors

  • These receptors bind to steroid hormones (e.g., testosterone, estrogen).

  • They exist in the cytosol in an inactive form bound to chaperones (e.g., HSP90) until hormone binding causes a conformational change, exposing the nuclear localization signal.

• Testosterone Receptor Action

  • The testosterone receptor, part of the androgen receptor family, binds testosterone and translocates to the nucleus to affect gene expression associated with male characteristics.

• Estrogen Receptor Action

  • Similar mechanism as the testosterone receptor; estrogen binding causes a conformational change and nuclear translocation.

Cytoskeletal Components

• Three Parts of Cytoskeleton

  • Actin Filaments (Microfilaments)

    • Located beneath the plasma membrane; important for structure and processes like endocytosis.

  • Microtubules

    • Composed of tubulin; involved in vesicular transport and cellular shape.

  • Intermediate Filaments

    • Provide tensile strength to cells; more stable without dynamic instability compared to microfilaments and microtubules.

• Intermediate Filament Structure

  • Comprised of coiled-coil structures forming tetramers which assemble into larger filament proteins providing structural integrity.

Interaction and Cell Adhesion

• Desmosomes

  • Specialized structures connecting neighboring cells; strengthened by intermediate filaments that help maintain the structural integrity during mechanical stress.

• Impact of Loss of Intermediate Filaments

  • Cells lacking intermediate filaments may tear under stress, demonstrating their critical role in cellular stability and adhesion.

Conclusion and Future Topics

• The interplay between different signaling pathways and cytoskeletal elements reflects an intricate biological network essential for maintaining cellular functions.