Week 5 A - Pathways of cell survival and growth control - pt 2 BI2BC45

Pathways of Cell Survival and Growth Control

  • Presenter: Dr. Mike Fry

  • Course: BI2BC45 – Cells and Immunity

  • Date: October 2022

Quick Recap of Previous Week

Integration of Multiple Signals

  • Key Concept: Multiple signals must integrate for a required response.

    • Important pathways include:

      • Ras

      • MAP kinase

      • PI 3-kinase

      • PKB/Akt

    • Functions affected:

      • Apoptosis

      • Cell Division

      • Cell Survival

  • Conclusion: Signals are stronger when combined.

Ras-MAP Kinase Pathway

  • Function: Growth factor activated signaling pathways used by many protein-tyrosine kinase (PTK) receptors.

  • Outcome: Changes in gene expression and modulation of the cell cycle.

Cyclin/CDK Control Points in Cell Cycle

  • Key Regulators:

    • Cyclins and Cyclin-dependent kinases (CDKs) work together to control cell cycle progression.

  • Components:

    • Cyclin D and CDK bundles at different phases:

      • CDK6 (G₁)

      • CDK4 (G₁)

      • CDK2 (S)

      • Mitosis controlled by Cyclin A and Cyclin B (CDK1).

Regulation of Myc Expression

  • Pathway: Ras-MAPK regulates Myc, which impacts gene expression.

  • Key Elements in Regulation:

    • Increased cyclin D expression through MYC

    • Activation of E2F and CDK pathways leads to G₁/S transition.

MYC, p53, and E2F Pathways

  • MYC Functions:

    • Controls cell-cycle progression, metabolism, and ribosome biogenesis.

  • p53 Role:

    • Involved in cell-cycle arrest and apoptosis in response to excessive Myc protein.

  • Key Interactions:

    • Excess Myc leads to p53 activation and cell cycle inhibition.

Growth Factors and the Cell Cycle

  • Mechanism: Growth factors regulate cell cycle via Cyclin D kinases.

    • Interactions with E2F promote transition from G1 to S phase.

  • Retinoblastoma Pathway:

    • Involves RB phosphorylation and its interactions with E2F proteins.

Role of PI 3-Kinase in Survival Signaling

  • PI 3-Kinase Functionality:

    • Integral in survival signals alongside growth factors.

  • Mechanisms of Action:

    • Involves integrins and various stimuli including fMLP and cytokines.

    • Functions include:

      • Oncogenic transformation

      • Protein trafficking

      • Regulation of cytoskeleton and insulin signaling.

PI 3-Kinase Activation and Substrate Interaction

  • Mechanisms:

    • Interacts with phosphatidylinositol lipids in the cell membrane.

  • Classes of PI3K:

    • Class IA: Activated by receptor tyrosine kinases.

    • Class IB: Activated by GPCRs.

Functional Domains of PI3K and Related Proteins

  • Lipid-Binding Domains:

    • PH domains, FYVE domains, PX domains facilitate signaling interactions.

  • Functional Roles:

    • In vesicle trafficking and cellular responses.

Signal Presence and Absence Effects

  • In Absence of Survival Factors:

    • Inhibition of apoptosis is lost, and BAD remains active.

  • In Presence of Survival Factors:

    • Receptor activation leads to PI3-kinase activation and reduced BAD activity, preventing apoptosis.

PDK1 and PKB Activation

  • Mechanism of Action:

    • PDK1 phosphorylates and activates PKB, which in turn phosphorylates various substrates on serine/threonine residues promoting survival.

  • Function of Activated PKB:

    • Inactivates pro-apoptotic proteins such as BAD.

Regulation and Inhibition Mechanisms

  • **Inhibition Pathways: **

    • Phosphatases like PTEN deactivate PIP3 and influence cell survival signaling.

  • MAPK and mTOR Integration:

    • Supports protein synthesis, growth, and survival pathways in response to environmental cues.

Additional Reading Suggestions

  • Review: BI1BEC1 Building blocks of life lecture - Cell signalling basics.

  • Reference: Molecular Biology of the Cell (5th Ed) - Chapter 15 on mechanisms of cell communication.