Cell Communication & Differentiation

Key Terms

Endocrine - Through the bloodstream to distant cells or organs

Paracrine - Diffuses through nearby tissue to nearby cells

Autocrine - Acts locally on the same cell.

Growth factors - Proteins that stimulate cells to grow, divide, survive & differentiate. They bind to receptors on the cell surface and trigger signalling pathways

Death signals - Chemical signals that instruct a cell to undergo programmed cell death

Cell-cell contact - Direct communication between neighbouring cells through physical contact using specialised proteins on their surfaces

Cell - extracellular matric contact - occurs when cells attach to the extracellular matrix (ECM), the network of proteins (such as collagen and fibronectin) surrounding cells.

Ligands - Signalling molecules - a molecule or ion that attaches to another atom or biological molecule through a specific interaction or bond.

Second Messenger - Mall molecule inside the cell that carriers the message onward.

Kinases - Attach to phosphate groups to a target proteins

Phosphorylation - Target protein changes the protein structure leading to a change in activity.

Phosphatases - Class of enzymes that reverse phosphorylation by removing the phosphate groups

Cell Communication

Why is it needed

  • Cells need to be interconnected and function in a coordinated manner to ensure proper functioning of tissues and organs


Key concepts

  • molecular recognition

  • Molecular switches

  • Signal amplification


Types of stimuli

  • Growth factors

  • Death signals

  • Dell-cell contact

  • Cell - extracellular matric contact

  • Hormones

  • Light (Photons)

  • Odorants

  • Touch

  • Oxygen levels

  • pH

  • Magnetic fields


  • Growth factors - Proteins that stimulate cells to grow, divide, survive & differentiate. They bind to receptors on the cell surface and trigger signalling pathways

  • Death signals - Chemical signals that instruct a cell to undergo programmed cell death

  • Cell-cell contact - Direct communication between neighbouring cells through physical contact using specialised proteins on their surfaces

  • Cell - extracellular matric contact - occurs when cells attach to the extracellular matrix (ECM), the network of proteins (such as collagen and fibronectin) surrounding cells.


Types of Direct Cell-Cell Signalling

  • Signalling by secreted molecules

    • Endocrine - Through the bloodstream to distant cells or organs

    • Paracrine - Diffuses through nearby tissue to nearby cells

    • Autocrine - Acts locally on the same cell.


Most cell communication involves the activation of specific receptor proteins via Ligands

  • Located in the plasma membrane.


Upon reception of a signal, the receptor is activated and transmits the signal into the cell

  • via a series of switches/relay molecules, called signal transduction, leading to a cellular response.

Reception of Signals

Most cell communication involves the activation of specific receptor proteins.

  • these are located in the cell membrane

  • receptors act as sensors that receive environmental cues and initiate a response within the cell.


Signal → receptor → intracellular signaling → cellular response



Types of receptors

  • lipophilic ligand → nuclear receptor

  • Matric - associated ligand

  • cell-matric adhesion receptor

  • cell adhesion molecule

  • nuclear receptor


Soluble ligand receptors

  • transporter

  • ion channel

  • G-protein coupled receptor

  • Enzyme-linked receptor

Receptor activation

Second Messenger - Mall molecule inside the cell that carriers the message onward.

Kinase - Adds phosphate
Phosphatase - Removes phosphate

Adding/removing phosphate can act like changing a protein's activity switch.


  • This change in the receptor acts as a signal for other enzymes to be recited to the receptor, allowing the signal to be relayed to other enzyme which amplifies the signal and pass it further into the cell

Receptor

Goes through second messenger?

Goes through kinases/phosphatases?

Main outcome

GPCR

Usually ✅

Usually ✅

Many types of cellular responses

Enzyme-linked receptor

Sometimes

Usually ✅

Growth, metabolism, gene expression, etc.

Ion channel

Usually ❌

Not necessarily

Rapid ion/electrical changes

Cell-matrix adhesion receptor

Sometimes

Often ✅

Cytoskeleton, adhesion, survival

Cell adhesion molecule

Sometimes

Often ✅

Cell-cell communication/organization

Nuclear receptor

❌

❌ usually

Direct changes in gene expression


Signal transduction

Cells have different receptor molecules as they don’t know what signals they may encounter.


- Signal amplification vis second messengers allows a weak signal to be amplified so that the cell can respond rapidly.


Examples of second messengers:

  • Cyclic AMP

  • Cyclic GMP

  • Inositol trisphosphate

  • Diacylglycerol

  • Calcium


Example Pathway - (Epinephrine signalling pathway)

  1. Epinephrine binds to GPCR causing it to change shape.

  2. G protein is activated which in turn activates adenylyl cyclase

  3. adenylyl cyclase is activated and converts ATP to cAMP

  4. cAMP is produced

  5. Protein kinase A is activated which activates phosphorylase kinase

  6. Phosphorylase kinase activates glycogen phosphorylase

  7. glycogen phosphorylase breaks down glycogen

  8. stored carbohydrate is mobilised so the cell can use it to help provide energy


Epinephrine → GPCR → G protein → adenylyl cyclase → ATP → cAMP → PKA → phosphorylase kinase → glycogen phosphorylase → glycogen breakdown → glucose-1-phosphate


Responding to signals

Kinases - Attach to phosphate groups to a target proteins

Phosphorylation - Target protein changes the protein structure leading to a change in activity.

Phosphatases - Class of enzymes that reverse phosphorylation by removing the phosphate groups


Post - Translational modification

Example - Protein phosphorylation

  • Addition of negative charged from the phosphate group to a protein can have significant effects on protein structure, leading to a conformational change

    • This typically occurs on - Serine, Threonine or tyrosine amino acids


Cellular Response - Insulin

  1. when the insulin receptor binds insulin

  2. the activated receptor phosphorylates the IRS-1 protein

  3. IRS-1 can lead to recruitment of GRB2

  4. activating the RAS pathway

  5. IRS-1 activates PI 3 - kinase which catalysis the addition of a phosphate group to the membrane lipid PIP2

  6. Converting PIP2 to PIP3

  7. PTEN can convert PIP3 back to PIP2

  8. PIP3 binds a protein kinase called AKt, which is activated by other protein kinases

  9. AKt catalysis phosphorylation of key proteins, leading to an increase in glycogen synthase activity and recruitment of the glucose transporter

  10. GLUT4 to the membrane

Dealing with multiple signals

Cell Differentiation

Each cell of the body ( expect from some exceptions) contain the same instructions as all the other cells.


Examples of specialised cells:

  • Bone ( osteoclasts and osteoblasts)

  • Venom Glands, duct and venom secreting cells

  • Eyes (light sensing cells, nerves, blood vessels, muscles, cornea)

  • chemical sensing cells (pit organ)

  • Epithelial cells ( lining of the mouth, scales)

  • muscle, nerves, blood vessels


Stem Cells

How do they develop

Mitosis produces 2 identical daughter cells

  • Differentiation - turning an undifferentiated , generalist cell (a stem cell ) into a differentiated, specialised cell.


Stem cells are capable of producing many types of differentiated cells

  • cell division is asymmetric - producing 2 different daughter cells


All stem cells are capable of self-renewal, but some are able to produce a wider range of cell types than others.


Types of Stem Cells

  • Totipotent - capable of producing any type of cell

  • Pluripotent - capable of producing any cell within a major lineage

  • Multi-potent - capable of producing a restricted set of related cells



Structure

  • Ectoderm - associated with outer surface nervous system

    • Brain and spinal cord

    • Nervous system

    • Skin (epidermis)

    • Hair and nails

    • Eyes and parts of the sensory organs

  • Mesoderm - Support, movement and transport structures

    • Heart and blood vessels#

    • Bones

    • Muscles

    • Connective tissue

    • Kidneys

    • Reproductive organs

    • Blood

  • Endoderm - linings of internal organs

    • Lungs and respiratory tract lining

    • Digestive tract lining

    • Liver

    • Pancreas

    • Thyroid (mainly the follicular cells)

    • Parts of the urinary and reproductive systems


Stem cells receive instructions in the form of differentiation signals, telling them what type of differentiated cell to produce.


These signals are received via cell surface receptors that transmit the signal into the cell, leading to changes in gene expression.


Stem cells have multiple different receptors and when one or more receptors are activated, it starts the process of differentiation.


Whether a specific gene (or set of genes) is expressed or silenced can be determined by the structure of chromatin.

•Euchromatin is lightly packed, making is accessible for transcription.

•Heterochromatin is tightly packed, making it difficult to transcribe genes in this region.


In stem cells, most of the DNA is found as lightly packed euchromatin, meaning that almost all of the genes are available for transcription.


As cells become differentiated, more and more genes become silenced in heterochromatin regions and only those needed to carry out the cell’s specialist function remain accessible in euchromatin.

Epigenetics

The switch between euchromatin and heterochromatin is controlled by enzymes that can attach methyl or acetyl groups either directly to DNA or to histone proteins that bind to DNA.


•DNA methylation silences genes

•Histone acetylation leads to euchromatin regions and increased gene expression

•Histone methylation can either increase or decrease gene expression depending on which parts of the histone protein are modified.


These epigenetic states (DNA/histone methylation or histone acetylation) can be inherited by daughter cells following mitosis