8  Cell Communication and Signaling

8.1 Learning Objectives

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

  1. Describe the basic principles of cell communication and its importance in multicellular organisms
  2. Classify different types of cell signaling based on distance and mechanism
  3. Explain the three stages of cell signaling: reception, transduction, response
  4. Describe major signal transduction pathways including GPCR, RTK, and steroid hormone pathways
  5. Analyze how signaling pathways are regulated and integrated within cells
  6. Explain how disruptions in cell signaling lead to diseases such as cancer
  7. Describe how cells communicate through direct contact and gap junctions
  8. Apply principles of cell signaling to understand physiological processes and therapeutic interventions

8.2 Introduction

Cells do not exist in isolation; they constantly communicate with each other and respond to environmental cues. Cell signaling allows cells to coordinate their activities, respond to changes, and maintain homeostasis. This chapter explores how cells send, receive, and interpret signals, transforming external information into intracellular responses. We will examine how signaling pathways implement the information processing principles introduced in Chapter 3, enabling cells to make decisions, adapt to conditions, and coordinate with neighboring cells in multicellular organisms.

8.3 Overview of Cell Communication

8.3.1 Importance of Cell Signaling

In multicellular organisms:

  • Coordinate development and growth
  • Regulate physiological processes
  • Maintain homeostasis
  • Enable immune responses
  • Facilitate neural communication

In unicellular organisms:

  • Coordinate group behaviors (quorum sensing)
  • Respond to environmental changes
  • Regulate cell cycle and reproduction

8.3.2 Evolution of Signaling Systems

Early evolution: Simple environmental sensing

Prokaryotic signaling: Two-component systems

Eukaryotic complexity: Multiple pathways with amplification and integration

Multicellular specialization: Development of specialized signaling cells

8.3.3 Basic Principles

  1. Specificity: Receptors bind specific ligands
  2. Amplification: Small signals produce large responses
  3. Integration: Multiple signals combined for coordinated response
  4. Desensitization/adaptation: Response diminishes with continued stimulation
  5. Modularity: Signaling components used in multiple pathways

8.4 Types of Cell Signaling

8.4.1 Based on Distance

Autocrine signaling: Cell signals itself

  • Example: Growth factors stimulating same cell that secreted them
  • Function: Amplification, positive feedback

Paracrine signaling: Signals nearby cells

  • Example: Neurotransmitters at synapses
  • Function: Local coordination

Endocrine signaling: Long-distance via bloodstream

  • Example: Hormones (insulin, estrogen)
  • Function: Systemic regulation

Synaptic signaling: Neuronal communication

  • Example: Neurotransmitters across synaptic cleft
  • Function: Rapid, specific communication

Contact-dependent signaling: Direct cell-cell contact

  • Example: Notch signaling during development
  • Function: Precise spatial control

8.4.2 Based on Signal Molecule

Hydrophobic signals: Cross membrane, bind intracellular receptors

  • Examples: Steroid hormones, thyroid hormones, retinoids
  • Receptors: Intracellular (cytoplasmic or nuclear)

Hydrophilic signals: Bind surface receptors

  • Examples: Peptide hormones, neurotransmitters, growth factors
  • Receptors: Membrane-bound

Gaseous signals: Diffuse through membranes

  • Examples: Nitric oxide, carbon monoxide
  • Action: Direct activation of intracellular enzymes

8.5 Stages of Cell Signaling

8.5.1 Stage 1: Reception

Signal molecule (ligand): Binds specifically to receptor

Receptor: Protein with binding site for specific ligand

Ligand-receptor interaction:

  • Non-covalent bonds (hydrogen, ionic, van der Waals)
  • High specificity and affinity
  • Reversible (except for some covalent modifications)

8.5.2 Stage 2: Transduction

Signal conversion: Extracellular signal → intracellular signal

Signal amplification: One ligand activates multiple intracellular molecules

Second messengers: Small intracellular signaling molecules

  • Examples: cAMP, cGMP, IP₃, DAG, Ca²⁺

Protein modifications:

  • Phosphorylation/dephosphorylation (kinases/phosphatases)
  • GTP binding (G proteins)
  • Conformational changes

8.5.3 Stage 3: Response

Cytoplasmic responses:

  • Altered metabolism
  • Changes in cytoskeleton
  • Altered secretion

Nuclear responses:

  • Changes in gene expression
  • Altered protein synthesis

Cell fate decisions:

  • Division
  • Differentiation
  • Apoptosis

8.6 Types of Receptors

8.6.1 G Protein-Coupled Receptors (GPCRs)

Structure: 7 transmembrane domains

Mechanism:

  1. Ligand binding activates receptor
  2. Receptor activates G protein
  3. G protein activates effector protein
  4. Effector produces second messenger

G proteins: Heterotrimeric (α, β, γ subunits)

  • Gα: GTPase activity, binds effector
  • Gβγ: Can also activate effectors

Major pathways:

  • cAMP pathway: Gαₛ → adenylyl cyclase → cAMP → PKA
  • Phospholipase C pathway: Gαq → PLC → IP₃ + DAG → Ca²⁺ release + PKC

Examples: Adrenergic receptors, olfactory receptors, rhodopsin

8.6.2 Receptor Tyrosine Kinases (RTKs)

Structure: Single transmembrane domain with extracellular ligand-binding and intracellular kinase domains

Mechanism:

  1. Ligand binding causes dimerization
  2. Cross-phosphorylation of tyrosine residues
  3. Phosphotyrosines serve as docking sites for signaling proteins
  4. Activation of multiple pathways

Major pathways:

  • Ras-MAPK pathway: Growth and differentiation
  • PI3K-Akt pathway: Cell survival and metabolism
  • PLCγ pathway: Ca²⁺ and PKC activation

Examples: Insulin receptor, EGF receptor, PDGF receptor

8.6.3 Ion Channel Receptors

Structure: Multipass transmembrane proteins forming channels

Mechanism:

  1. Ligand binding opens channel
  2. Ions flow down electrochemical gradient
  3. Changes membrane potential or ion concentration

Types:

  • Ligand-gated ion channels: Neurotransmitter receptors
  • Voltage-gated ion channels: Action potentials
  • Mechanically-gated ion channels: Touch, hearing

Examples: Nicotinic acetylcholine receptor, GABAₐ receptor

8.6.4 Intracellular Receptors

Location: Cytoplasm or nucleus

Ligands: Small hydrophobic molecules (steroids, thyroid hormones)

Mechanism:

  1. Ligand crosses membrane by diffusion
  2. Binds receptor, causing conformational change
  3. Receptor-ligand complex enters nucleus (if not already there)
  4. Binds DNA, regulates gene expression

Examples: Estrogen receptor, glucocorticoid receptor

8.6.5 Other Receptor Types

Receptor serine/threonine kinases: TGF-β receptors

Receptor guanylyl cyclases: Atrial natriuretic peptide receptor

Histidine kinase receptors: Two-component systems in bacteria and plants

8.7 Signal Transduction Pathways

8.7.1 cAMP Pathway

Components:

  • GPCR: Stimulatory (Gαₛ) or inhibitory (Gαᵢ)
  • Adenylyl cyclase: Produces cAMP from ATP
  • Protein Kinase A (PKA): Activated by cAMP
  • Phosphodiesterase: Degrades cAMP to AMP

Effects:

  • Glycogen breakdown (in liver, muscle)
  • Fat breakdown (in adipose tissue)
  • Water conservation (in kidney)
  • Increased heart rate and contractility

Example: Epinephrine action via β-adrenergic receptors

8.7.2 Phospholipase C Pathway

Components:

  • GPCR: Gαq type
  • Phospholipase C (PLC): Cleaves PIP₂ to IP₃ + DAG
  • IP₃: Releases Ca²⁺ from ER
  • DAG: Activates PKC
  • Ca²⁺: Binds calmodulin, activates CaMK

Effects:

  • Smooth muscle contraction
  • Glycogen breakdown
  • Neuronal signaling
  • Cell proliferation

Example: Vasopressin action in smooth muscle

8.7.3 Ras-MAPK Pathway

Components:

  • RTK: Activated by growth factors
  • Grb2-SOS complex: Activates Ras
  • Ras: Small GTPase
  • MAPK cascade: Raf → MEK → ERK

Effects:

  • Cell growth and division
  • Differentiation
  • Survival

Example: EGF stimulation of cell proliferation

8.7.4 PI3K-Akt Pathway

Components:

  • RTK: Activates PI3K
  • PI3K: Phosphorylates PIP₂ to PIP₃
  • PIP₃: Recruits Akt (PKB) to membrane
  • Akt: Activated by phosphorylation

Effects:

  • Cell survival (inhibits apoptosis)
  • Protein synthesis
  • Glucose uptake

Example: Insulin action on glucose metabolism

8.7.5 JAK-STAT Pathway

Components:

  • Cytokine receptors: Associated with JAK kinases
  • JAK: Janus kinases, phosphorylate receptors
  • STAT: Signal transducers and activators of transcription

Effects:

  • Immune responses
  • Hematopoiesis
  • Growth and development

Example: Interferon signaling

8.7.6 Wnt/β-catenin Pathway

Components:

  • Wnt ligand: Binds Frizzled receptor
  • β-catenin: Normally degraded, stabilized by Wnt
  • TCF/LEF: Transcription factors activated by β-catenin

Effects:

  • Embryonic development
  • Cell fate determination
  • Stem cell maintenance

Example: Embryonic patterning

8.7.7 Notch Pathway

Components:

  • Notch receptor: Single-pass transmembrane
  • Delta/Jagged ligands: On neighboring cells
  • Proteolytic cleavage: Releases Notch intracellular domain (NICD)
  • NICD: Enters nucleus, regulates transcription

Effects:

  • Cell fate decisions
  • Lateral inhibition
  • Development

Example: Neurogenesis in Drosophila

8.8 Second Messengers

8.8.1 cAMP (cyclic AMP)

Synthesis: Adenylyl cyclase from ATP

Degradation: Phosphodiesterase to AMP

Target: Protein Kinase A (PKA)

Effects: Wide range through phosphorylation of various proteins

8.8.2 cGMP (cyclic GMP)

Synthesis: Guanylyl cyclase from GTP

Target: Protein Kinase G (PKG), phosphodiesterases, ion channels

Effects: Smooth muscle relaxation, phototransduction

8.8.3 Calcium Ions (Ca²⁺)

Sources: ER release, extracellular influx

Regulation: Pumps, channels, buffers

Targets: Calmodulin, protein kinase C, other Ca²⁺-binding proteins

Effects: Muscle contraction, secretion, synaptic transmission

8.8.4 IP₃ (Inositol trisphosphate) and DAG (Diacylglycerol)

Source: PLC cleavage of PIP₂

IP₃ action: ER Ca²⁺ release

DAG action: PKC activation

Effects: Diverse cellular responses

8.8.5 Other Second Messengers

Nitric oxide (NO): Activates guanylyl cyclase

Reactive oxygen species (ROS): Signaling in stress responses

Phosphatidylinositol phosphates: Membrane localization signals

8.9 Signaling Networks and Integration

8.9.1 Cross-Talk Between Pathways

Definition: Interaction between different signaling pathways

Mechanisms:

  • Shared components
  • Regulatory phosphorylation between pathways
  • Convergent targets
  • Pathway inhibition/activation

Examples:

  • cAMP can inhibit Raf in MAPK pathway
  • PKC can phosphorylate RTKs
  • Ca²⁺ can activate adenylyl cyclase

8.9.2 Signal Amplification

Cascade amplification: Each step activates multiple next components

Example: Epinephrine signal amplification

  • One epinephrine molecule → hundreds of cAMP molecules
  • Each PKA activates multiple enzymes
  • Overall amplification: ~10⁸-fold

8.9.3 Signal Duration and Termination

Mechanisms for termination:

  1. Ligand degradation or removal
  2. Receptor desensitization (phosphorylation, internalization)
  3. G protein inactivation (GTP hydrolysis)
  4. Second messenger degradation
  5. Phosphatase action
  6. Negative feedback loops

Adaptation: Response declines despite continued stimulus

8.9.4 Scaffolding Proteins

Function: Organize signaling components

Benefits:

  • Increase efficiency
  • Prevent cross-talk
  • Ensure specificity
  • Localize signals

Examples:

  • Ste5: In yeast MAPK pathway
  • AKAPs: Anchor PKA to specific locations
  • InaD: In Drosophila phototransduction

8.10 Cell-Cell Communication

8.10.1 Gap Junctions

Structure: Connexin hexamers forming channels between cells

Function: Direct exchange of small molecules (<1 kDa)

Regulation: pH, Ca²⁺, voltage, phosphorylation

Importance: Electrical coupling, metabolic cooperation, development

8.10.2 Plasmodesmata (Plants)

Structure: Membrane-lined channels through cell walls

Function: Transport of molecules, viruses, signaling molecules

Regulation: Size exclusion limit, callose deposition

8.10.3 Direct Contact Signaling

Juxtacrine signaling: Membrane-bound ligand to receptor on adjacent cell

Examples:

  • Notch-Delta: Developmental patterning
  • Ephrin-Eph: Axon guidance
  • Cadherins: Cell adhesion and signaling

8.10.4 Extracellular Matrix (ECM) Signaling

Integrins: Connect ECM to cytoskeleton, initiate signaling

Mechanotransduction: Convert mechanical forces to biochemical signals

Functions: Cell adhesion, migration, differentiation, survival

8.11 Signaling in Development and Disease

8.11.1 Developmental Signaling

Morphogens: Concentration gradients determine cell fate

  • Examples: Bicoid in Drosophila, Sonic hedgehog in vertebrates
  • French flag model: Different thresholds activate different genes

Pattern formation: Coordinate expression of Hox genes

Apoptosis signaling: Programmed cell death during development

8.11.2 Cancer and Signaling

Oncogenes: Mutated forms of normal signaling proteins

  • Examples: Ras, Src, Myc
  • Mechanism: Constitutively active, promote growth

Tumor suppressor genes: Normally inhibit growth

  • Examples: p53, Rb, PTEN
  • Mechanism: Loss of function allows uncontrolled growth

Common alterations:

  • Growth factor overexpression
  • Receptor mutations (constitutive activation)
  • Ras mutations (GTPase deficient)
  • p53 mutations (loss of cell cycle control)

8.11.3 Therapeutic Interventions

Targeted therapies:

  • Receptor antagonists: Block ligand binding
  • Tyrosine kinase inhibitors: Imatinib (Gleevec) for CML
  • Monoclonal antibodies: Trastuzumab (Herceptin) for HER2+ breast cancer

Challenges: Resistance, specificity, side effects

8.12 Chapter Summary

8.12.1 Key Concepts

  1. Cell signaling allows cells to communicate and coordinate activities
  2. Three stages: Reception → transduction → response
  3. Major receptor types: GPCRs, RTKs, ion channels, intracellular receptors
  4. Signal transduction pathways use second messengers and protein modifications
  5. Signaling networks integrate multiple inputs for coordinated responses
  6. Cell-cell communication occurs through gap junctions, direct contact, and secreted signals
  7. Dysregulated signaling underlies many diseases including cancer

8.12.2 Comparison of Major Pathways

Pathway Receptor Type Key Components Major Functions
cAMP GPCR (Gαₛ/Gαᵢ) AC, cAMP, PKA Metabolism, cardiac function
PLC GPCR (Gαq) PLC, IP₃, DAG, Ca²⁺ Contraction, secretion
Ras-MAPK RTK Ras, Raf, MEK, ERK Growth, differentiation
PI3K-Akt RTK PI3K, PIP₃, Akt Survival, metabolism
Steroid Intracellular Hormone-receptor complex Gene expression

8.12.3 Principles of Signaling

  1. Specificity: Ligand-receptor specificity
  2. Amplification: Signal amplification through cascades
  3. Integration: Multiple signals combined
  4. Desensitization: Response adaptation
  5. Modularity: Components reused in different pathways
  6. Cross-talk: Pathway interactions
  7. Feedback: Positive and negative regulation

8.12.4 Quantitative Aspects

Affinity: Kd typically 10^-9 to 10^-12 M Amplification: Up to 10⁸-fold in some pathways Response time: Milliseconds (ion channels) to hours (gene expression) Sensitivity: Can detect single molecules in some systems

8.13 Review Questions

8.13.1 Level 1: Recall and Understanding

  1. Name the three stages of cell signaling and describe what happens in each.
  2. Compare and contrast GPCRs and RTKs in terms of structure and mechanism.
  3. List four types of second messengers and their functions.
  4. What are gap junctions and what is their role in cell communication?
  5. Define the terms: ligand, receptor, second messenger, signal transduction.

8.13.2 Level 2: Application and Analysis

  1. Trace the steps from epinephrine binding to glycogen breakdown in liver cells.
  2. How does the Ras-MAPK pathway become constitutively active in cancer?
  3. Explain how calcium acts as a second messenger in muscle contraction.
  4. Compare autocrine, paracrine, and endocrine signaling.
  5. Design an experiment to determine whether a signaling pathway uses cAMP as a second messenger.

8.13.3 Level 3: Synthesis and Evaluation

  1. Evaluate the statement: “Cancer is primarily a disease of cell signaling.”
  2. How do cells integrate multiple simultaneous signals to produce a coordinated response?
  3. Compare the evolutionary advantages of simple vs. complex signaling systems.
  4. Design a therapeutic strategy targeting a specific signaling pathway for cancer treatment.

8.14 Key Terms

  • Signal transduction: Process of converting extracellular signals into intracellular responses
  • Ligand: Signaling molecule that binds specifically to a receptor
  • Receptor: Protein that binds ligand and initiates cellular response
  • G protein-coupled receptor (GPCR): Receptor with 7 transmembrane domains that activates G proteins
  • Receptor tyrosine kinase (RTK): Receptor that phosphorylates tyrosine residues upon activation
  • Second messenger: Small intracellular signaling molecule
  • Protein kinase: Enzyme that phosphorylates proteins
  • Phosphatase: Enzyme that removes phosphate groups from proteins
  • Amplification: Increase in signal strength through a cascade
  • Cross-talk: Interaction between different signaling pathways
  • Scaffolding protein: Protein that organizes signaling components
  • Gap junction: Channel connecting cytoplasm of adjacent cells
  • Autocrine signaling: Cell signals itself
  • Paracrine signaling: Signaling to nearby cells
  • Endocrine signaling: Long-distance signaling via bloodstream

8.15 Further Reading

8.15.1 Books

  1. Alberts, B., et al. (2022). Molecular Biology of the Cell (7th ed.). W. W. Norton & Company.
  2. Gomperts, B. D., et al. (2009). Signal Transduction (2nd ed.). Academic Press.
  3. Bradshaw, R. A., & Dennis, E. A. (Eds.). (2010). Handbook of Cell Signaling (2nd ed.). Academic Press.

8.15.2 Scientific Articles

  1. Sutherland, E. W. (1972). Studies on the mechanism of hormone action. Science, 177(4047), 401-408.
  2. Hunter, T. (2000). Signaling—2000 and beyond. Cell, 100(1), 113-127.
  3. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646-674.

8.15.3 Online Resources

  1. Signal Transduction Knowledge Environment: https://stke.sciencemag.org
  2. Cell Signaling Technology Pathways: https://www.cellsignal.com
  3. Reactome Pathway Database: https://reactome.org

8.16 Quantitative Problems

  1. Signal Amplification:

    In the epinephrine signaling pathway:

    1. If one epinephrine molecule activates 100 G proteins, each activating 10 adenylyl cyclase molecules, each producing 1000 cAMP molecules, each activating 10 PKA molecules, each phosphorylating 100 target proteins, what is the total amplification?
    2. If liver cells have 10,000 β-adrenergic receptors, how many glycogen phosphorylase molecules could be activated by saturating epinephrine?

  2. Receptor-Ligand Kinetics:

    A receptor has Kd = 10^-9 M for its ligand.

    1. What fraction of receptors is occupied at [ligand] = 10^-9 M, 10^-8 M, 10^-10 M?
    2. If there are 1000 receptors/cell and ligand concentration is 10^-9 M, how many receptors are occupied?
    3. How does affinity relate to biological sensitivity?

  3. Calcium Signaling:

    Resting cytosolic [Ca²⁺] = 100 nM. During signaling, it rises to 1 μM.

    1. If cell volume is 1000 μm³, how many Ca²⁺ ions enter?
    2. If each IP₃ receptor releases 10,000 Ca²⁺ ions, how many receptors need to open?
    3. What percentage of ER Ca²⁺ is released if total ER [Ca²⁺] = 1 mM?

8.17 Case Study: Diabetes and Insulin Signaling

Background: Type 2 diabetes involves insulin resistance in target tissues.

Questions:

  1. Trace the insulin signaling pathway from receptor binding to glucose uptake.
  2. How might mutations in insulin receptor, IRS-1, or PI3K cause insulin resistance?
  3. Why do some tissues become insulin resistant while others don’t?
  4. Design experiments to identify which step in insulin signaling is defective in a patient with insulin resistance.

Data for analysis:

  • Insulin receptor: RTK with α₂β₂ structure
  • Key steps: Receptor autophosphorylation, IRS phosphorylation, PI3K activation, Akt activation, GLUT4 translocation
  • In diabetes: Reduced receptor number, defective signaling, impaired GLUT4 translocation
  • Treatments: Improve insulin sensitivity, enhance secretion, alternative pathways

End of Part II: Cellular Systems

Next Part: Part III: Genetics & Molecular Biology