L7 Cancer Cell Signaling

BIOL3064/6071 Lecture Notes: Cancer Cell Signaling

Next 3 Lectures

  1. Cancer Signaling Lecture 1: Cell signaling and cancer: an introduction

  2. Cancer Signaling Lecture 2: Molecular architecture of signaling pathways

  3. Cancer Signaling Lecture 3: The Wnt signaling pathway and cancer

Learning Outcomes

By the end of this session, you should be able to:

  • Describe the principles of cell signaling

  • Explain how cancer cells rely on signaling pathways for proliferation and survival

  • Describe how information is processed through signaling networks

  • Explain how post-translational modifications alter signaling events

  • Define the different types of feedback mechanisms that regulate cell signaling

Key Questions for Lecture 1

  • Why is signaling so important to cancer cells?

  • What are signaling pathways and networks?

Importance of Cell Signaling in Cancer

Cell Signaling Principles

  • Cell signaling is crucial for cells to make decisions based on environmental cues such as metabolites, hormones, and the presence of other cells or pathogens.

  • Cells use signaling to respond to their state and surroundings, impacting decisions about proliferation or apoptosis (cell death).

Cancer Cell Characteristics

  • Chronic proliferation is a fundamental trait of cancer cells, as noted by Hanahan and Weinberg in their Hallmarks of Cancer.

  • Altered signaling is present in most cancers, characterized by

    • Activation of signaling pathways that are unresponsive to inhibitors

    • Increased signaling volumes

    • Activation at inappropriate times or locations

  • These alterations allow cancer cells to evade normal regulatory controls.

Contribution of Oncogenes and Tumor Suppressors

Oncogenes

  • Oncogenes are capable of cellular transformation leading to cancer.

  • They are derived from proto-oncogenes typically through mutation or overproduction.

  • Oncogenes encode oncoproteins, which function as part of cell signaling pathways, including as receptors.

Tumor Suppressors

  • Tumor suppressor genes suppress or control cell proliferation.

  • Mutations in these genes typically lead to loss of function (often recessive), thus removing inhibition.

  • They encode proteins with diverse roles, particularly in regulating the cell cycle, apoptosis, and signaling.

Cancer, Signaling, and Drug Development

  • Many drug targets in cancer treatment are signaling molecules.

  • New targeted therapies mostly focus on signaling proteins:

    • Monoclonal antibodies (e.g., Herceptin in breast cancer) inhibit growth factor receptors.

    • Tyrosine kinase inhibitors (e.g., Imatinib [Gleevec] in chronic myelogenous leukaemia targeting BCR-Abl) are other examples.

Research in Cell Signaling

  • Research in signaling is fundamental and shows that many oncogenes encode mutant versions of signaling processes.

  • Understanding signaling through oncogenes has been pivotal in elucidating these processes.

Evolutionary Conservation of Signaling

  • Signaling pathways are conserved throughout animal evolution.

  • Model systems are utilized to study cancer signaling, as many of these pathways play crucial roles in embryonic development (e.g., Wnt, Notch, Hedgehog, TGF-Beta).

Information Processing in Cell Signaling

Overview

  • Cell Signaling Definition: The mechanisms through which cells perceive and adapt to their surroundings.

  • Signal Transduction: The biochemical process that facilitates information processing within cells.

  • Quote by R.A. Weinberg: "Signal transduction biochemistry is a field afflicted with many facts and blessed with only a few unifying principles."

Cell as Information Processing Devices

  • Cells can be viewed as information processing devices with inputs, a decision-making system, and outputs.

  • Key proteins and molecules involved in these processes include:

    • Input Layer: Ligands (e.g., LPA, EGF, cytokines) and receptors (e.g., cell surface receptors)

    • Signaling Cascades: A network of interconnected signaling proteins (e.g., RAS, PI3K, MAPK) facilitating signal transduction

    • Output Layer: Transcription factors mediating processes such as apoptosis, migration, growth, and differentiation.

Challenges in Cell Signaling Information Processing

Key Challenges

  • Cells face several challenges in processing information:

    • Signal transmission through the plasma membrane, which acts as a barrier

    • Achieving specificity of response to signals

    • Signal amplification for effective communication

    • Coordinating and integrating multiple signals simultaneously

Cell Signaling Pathways

  • Information is processed through cascades of molecular events, connecting sequentially in a series.

  • Example pathways relevant to cancer include:

    • Ras Signaling Pathway

    • Wnt Signaling Pathway

  • These cascades allow for perception and transmission of cellular information and are integral to cancer development.

Mechanisms of Information Transmission

  • Information conveyed through various mechanisms:

    • Nucleocytoplasmic shuttling

    • Protein phosphorylation

    • G-protein activity (GTP/GDP binding)

    • Ligand-receptor interactions

  • Proteins in signaling pathways act as switches that can change states to either transmit or record information.

Post-Translational Modifications (PTMs) and Protein State

Overview of PTMs

  • Post-Translational Modifications (PTMs): These are critical in altering protein states, enabling regulation of signaling dynamics in cellular processes.

  • Common types include phosphorylation, acetylation, methylation, and ubiquitination.

Modulating Protein Function

  • Writers (Kinases): Add phosphate groups to proteins, thus activating or inactivating them.

  • Erasers (Phosphatases): Remove phosphate groups, which can reverse the action of kinases.

  • Approximately 30% of human proteins can be phosphorylated, highlighting the importance of PTMs in cellular signaling.

Complex Dynamics of Signaling Pathways

Signaling Pathway Dynamics

  • Signaling pathways involve multiple scales of operation:

    • Plasma Membrane Events: Initial receptor activation and signal transduction.

    • Cytoplasmic Events: Amplification and relay of signals through intracellular signaling proteins.

    • Nuclear Events: Regulation of gene expression and transcriptional programming.

  • Feedback mechanisms are essential to maintain pathway activity and contribute to homeostasis:

    • Negative Feedback: Reduces signaling activity when levels exceed a set point.

    • Positive Feedback: amplifies the signal, which can lead to an enhanced response.

Feedback Mechanisms in Signaling Pathways

Mechanisms of Feedback

  • Negative Feedback: Helps in maintaining signaling within a specific range (homeostasis) by counteracting excess signal.

  • Positive Feedback: Leading to the amplification and stabilization of a specific signal, thus enhancing response.

Signaling Pathways vs. Signaling Networks

Integration of Signaling Pathways

  • Signaling pathways are often interconnected, forming a complex network of interactions rather than isolated sequences.

  • Different types of integration include:

    • Convergence: Multiple signals activating a common pathway (e.g., Ras).

    • Divergence: A single signal producing various outcomes through different pathways.

    • Cross-talk: Interaction between different signaling pathways that allow for integrated cellular responses.

Key Components in Signaling Networks

Molecular Participants

  • Signaling Receptors: Particularly transmembrane receptors (e.g., Receptor Tyrosine Kinases - RTKs) that facilitate signal transduction across the membrane.

  • Kinases and Phosphatases: Enzymes that modify proteins via phosphorylation, central to many signaling events.

  • Transcription Factors: Directly involved in mediating transcriptional regulation in response to signaling events.

Receptor Tyrosine Kinases (RTKs)

RTKs Overview

  • RTKs are receptors characterized by intrinsic tyrosine kinase activity and serve as crucial mediators in cell signaling.

  • Common RTKs include those activated by various ligands such as growth factors and hormones.

Mechanisms of Dimerization and Activation

  • RTKs dimerize upon ligand binding, leading to conformational changes which enable autophosphorylation and recruitment of further signaling proteins.

Oncogenic Mutations in RTKs

  • Mutations can lead to enhanced signaling (e.g., ligand-independent activation, overexpression) contributing to oncogenesis.

  • Example: EGFR mutations, where alterations in copy number amplify receptor expression and signal transduction.

Phosphorylation and Signaling

Functional Consequences of Phosphorylation

  • Phosphorylation of proteins leads to several functional outcomes:

    • Induction of conformational changes

    • Activation or inactivation of protein function

    • Regulation of protein-protein interactions

    • Changes in sub-cellular localization

    • Modulation of degradation pathways via the proteasome

Complexity of Post-translational Modifications

  • Various PTMs interact in complex ways, affecting signaling pathways and their dynamics.

  • PTMs can synergize (promote each other) or antagonize (inhibit each other), creating a sophisticated regulatory environment for cellular processes.

Proteasome Function in Signaling

Key Role in Degradation

  • The ubiquitin-proteasome system is crucial for rapid degradation of signaling proteins, influencing signaling cascades.

  • PTMs can mark proteins for degradation or stability based on signaling needs and cellular contexts.

Wnt Signaling Overview

Introduction to Wnt

  • Wnt signaling is critical in normal development and aberrations often lead to various cancers.

  • Both canonical (β-catenin dependent) and non-canonical pathways exist to mediate signaling, with distinct roles in development and disease.

Canonical Wnt Pathway

  • Involves β-catenin as a key effector, where Wnt signaling prevents its degradation.

  • Regulates crucial processes including cell proliferation and differentiation, particularly in colorectal cancer.

Aberrant Wnt Signaling and Diseases

Consequences of Dysregulated Wnt Signaling

  • Dysregulation can lead to multiple diseases including cancer and other developmental disorders.

    • Colorectal cancer due to inappropriate Wnt signaling activity.

    • Neural tube defects from improper signaling during embryogenesis.

    • High bone density or other skeletal abnormalities linked to altered signaling.

Wnt Pathway Components

Key Protein Interactions

  • Interaction among several proteins (e.g., Frizzled, LRP5/6) mediates Wnt signaling.

  • The destruction complex regulates β-catenin levels, which if disrupted, contributes to cancer development.

Therapeutic Strategies Targeting Wnt

Potential Drugs and Approaches

  • Research is ongoing to develop drugs that can modulate Wnt signaling, either inhibiting or enhancing the pathway based on the disease context (e.g., colorectal cancer approaches).

Conclusion

Summary of Key Points

  • Wnt signaling plays a pivotal role in development and its dysregulation is a driving factor in numerous cancers.

  • Understanding and targeting underlying signaling pathways can yield significant therapeutic innovations in cancer treatment.