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�Cell Communication

Cell-to-cell communication is essential for both multicellular and unicellular organisms

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Overview: Evolution of signaling

Biologists have discovered some universal mechanisms of cellular regulation
Cells most often communicate with each other via chemical signals

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Evolution :

Microbes provide a glimpse of the role of cell signaling in the evolution of life

Exchange �of mating �factors

Mating

New a/α cell

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Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes

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I. Local and Long-Distance Signaling

Cells in a multicellular organism communicate by chemical messengers
Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells

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In local signaling, animal cells may communicate by direct contact, or cell-cell recognition

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In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances

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In long-distance signaling, plants and animals use chemicals called hormones

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The ability of a cell to respond to a signal depends on whether or not it has a receptor specific to that signal

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II. Signal Transduction Pathway - a series of steps by which a signal on a cell’s surface is converted into a specific cellular response

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Figure 11.1

Example - the fight-or-flight response is triggered by a signaling molecule called epinephrine

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Figure 11.1

Cellular response to epinephrine is different in different cell types:

smooth muscle of most blood vessels - constricts

smooth muscle of blood vessels in skeletal muscle and liver - dilation

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Figure 11.1

heart muscle - rate of contraction increases; force of contraction increases

liver - glycogen broken down to glucose,

smooth muscle in iris of eye - contracts causing dilation of the pupil

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Plasma membrane

EXTRACELLULAR�FLUID

CYTOPLASM

Reception

Transduction

Response

Receptor

Signaling�molecule

Activation�of cellular�response

Relay molecules in a signal transduction�pathway

3

2

1

The Three Stages of Cell Signaling

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A. Reception: A signaling molecule binds to a receptor protein, causing it to change shape

The binding between a chemical messenger (ligand) and receptor is highly specific (one to one relationship)
The ligand can be a peptide, a small chemical, or protein or steroid

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A shape change (conformational change) in a receptor is often the initial transduction of the signal

Most signal receptors are plasma membrane proteins

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Receptors are proteins. What are the monomers?

Amino acids (amino group, carboxylic acid group, side chain/R group)

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Significance of the amino acid side chains in a receptor

Their charges (or lack thereof) impact the receptor’s interactions with specific ligands

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1. Receptors in the Plasma Membrane

Most water-soluble ligands bind to receptor proteins that span the plasma membrane

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A protein domain is a region of the protein's polypeptide chain that is self-stabilizing and that folds independently from the rest.

Ligand binding domain of the receptor protein

Intramembranous domain of the receptor protein

Intracellular domain (cytoplasmic domain) of the receptor protein

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There are 3 main types of membrane receptors

G protein-coupled receptors
Receptor tyrosine kinases
Ion channel receptors

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a. G-protein-coupled receptor (GPCRs) are the largest family of cell-surface receptors

It works with the help of a G protein
The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive

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animation canva

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When ligand binds to this receptor, there is a conformational change in the receptor’s intracellular domain

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Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines (an amino acid)

Kinase - an enzyme that phosphorylates another molecule

animation

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A receptor tyrosine kinase can trigger multiple signal transduction pathways at once

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c. A ligand-gated ion channel receptor acts as a gate when the receptor changes shape

When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na⁺ or Ca²⁺, through a channel in the receptor

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When ligand binds to this receptor, there is a conformational change that opens or closes a protein’s transport channel

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Hormone�(testosterone)

Receptor�protein

Plasma�membrane

DNA

NUCLEUS

CYTOPLASM

EXTRACELLULAR�FLUID

Intracellular receptor proteins are found in the cytosol or nucleus of target cells

2. Intracellular Receptors

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Hormone�(testosterone)

Receptor�protein

Plasma�membrane

Hormone-�receptor�complex

DNA

NUCLEUS

CYTOPLASM

EXTRACELLULAR�FLUID

Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors

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Hormone�(testosterone)

Receptor�protein

Plasma�membrane

Hormone-�receptor�complex

DNA

NUCLEUS

CYTOPLASM

EXTRACELLULAR�FLUID

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Hormone�(testosterone)

Receptor�protein

Plasma�membrane

Hormone-�receptor�complex

DNA

mRNA

NUCLEUS

CYTOPLASM

EXTRACELLULAR�FLUID

An activated hormone-receptor complex can act as a transcription factor, turning on specific genes

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Hormone�(testosterone)

Receptor�protein

Plasma�membrane

EXTRACELLULAR�FLUID

Hormone-�receptor�complex

DNA

mRNA

NUCLEUS

CYTOPLASM

New protein

Examples of hydrophobic messengers are the steroid and thyroid hormones of animals

(animation summary)

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B. Transduction: Cascades of molecular interactions that link ligand binding to target cell response

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1. Goals of signal transduction:

Ensuring that target cells have the appropriate response to ligand binding

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Multistep pathways can amplify a signal: A few molecules can produce a large cellular response

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The amplification might be shown with thickness of arrows, rather than numbers

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Multistep pathways provide more opportunities for coordination and regulation of the cellular response

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Coordination: Protein Y needs phosphorylation at both locations to be activate. It becomes active only when ligands A and B are both present.

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2. Important molecules and common processes in signal transduction pathways

The molecules that relay a signal from receptor to response are mostly proteins
Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated

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In many pathways, the signal is transmitted by a cascade of protein phosphorylations

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Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation

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There are many steps in the cascade in order to amplify the signal or regulate it at various different steps.

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Figure 11.10a

Activated relay�molecule

Phosphorylation cascade

Inactive�protein kinase�1

Active�protein �kinase�1

Active�protein �kinase�2

Active�protein �kinase�3

Inactive�protein kinase�2

Inactive�protein kinase�3

Inactive�protein

Active�protein

ATP

ADP

ATP

ADP

ATP

ADP

PP

P

P _i

P

Protein phosphatases remove the phosphates from proteins (dephosphorylation) which often inactivates the proteins

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Figure 11.10a

Activated relay�molecule

Phosphorylation cascade

Inactive�protein kinase�1

Active�protein �kinase�1

Active�protein �kinase�2

Active�protein �kinase�3

Inactive�protein kinase�2

Inactive�protein kinase�3

Inactive�protein

Active�protein

ATP

ADP

ATP

ADP

ATP

ADP

PP

P

P _i

P

This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required

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Phosphorylation causes conformational changes in the protein, activating (or deactivating) the protein.

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The energy required for phosphorylation catalyzed by kinases comes from the hydrolysis of ATP

covalent bond

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Dephosphorylation generally does not require energy

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Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion

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Cyclic AMP (cAMP) and calcium ions are common second messengers

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Figure 11.12

G protein

First messenger�(signaling molecule�such as epinephrine)

G protein-coupled�receptor

Adenylyl�cyclase

Second �messenger

Cellular responses

Protein�kinase A

GTP

ATP

cAMP

Adenylyl cyclase is an enzyme that converts ATP to cAMP in response to an extracellular signal

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Calcium ions (Ca²⁺) act as a second messenger in many pathways

https://www.youtube.com/watch?v=OWEThbwaoPc

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Relay proteins - pass signals along from the receptor into the cell, often forming chains to amplify and modify the original message

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Figure 11.14-3

G protein

EXTRA-�CELLULAR�FLUID

Signaling molecule�(first messenger)

G protein-coupled�receptor

Phospholipase C

DAG

PIP₂

IP_{3 �}(second messenger)

IP₃-gated�calcium channel

Endoplasmic�reticulum (ER)

CYTOSOL

Various�proteins�activated

Cellular�responses

Ca²⁺�(second�messenger)

Ca²⁺

GTP

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C. Response: target cell is altered

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Examples of Cellular Responses:

A response might be to make a transcription factor which turns on a gene

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A response might be to repress the transcription of a gene

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A response might be to regulate the activity of enzymes

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A response might be to change the overall shape of a cell

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Figure 11.17

Wild type (with shmoos)

ΔFus3

Δformin

Mating�factor�activates�receptor.

Mating�factor

G protein-coupled�receptor

Shmoo projection�forming

Formin

G protein binds GTP�and becomes activated.

2

1

3

4

5

P

Formin

Fus3

GDP

GTP

Phosphory-� lation� cascade

Microfilament

Actin�subunit

Phosphorylation cascade�activates Fus3, which moves

to plasma membrane.

Fus3 phos-�phorylates�formin,�activating it.

Formin initiates growth of�microfilaments that form�the shmoo projections.

RESULTS

CONCLUSION

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A response might be to secrete something

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A response might be cell division or differentiation

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The response might be programmed or controlled cell death (apoptosis) animation

Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells

Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells

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Interdigital tissue

Cells undergoing�apoptosis

Space between�digits

1 mm

Apoptosis is a normal part of development

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Figure 11.21a

Mitochondrion

Ced-9�protein (active)�inhibits Ced-4�activity

Receptor�for death-�signaling�molecule

Ced-4

Ced-3

Inactive proteins

(a) No death signal

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Figure 11.21b

Death-�signaling�molecule

Ced-9�(inactive)

Cell�forms�blebs

Active�Ced-4

Active�Ced-3

Other�proteases

Nucleases

Activation�cascade

(b) Death signal

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Figure 11.21

Mitochondrion

Ced-9�protein (active)�inhibits Ced-4�activity

Receptor�for death-�signaling�molecule

Ced-4

Ced-3

Inactive proteins

(a) No death signal

Death-�signaling�molecule

Ced-9�(inactive)

Cell�forms�blebs

Active�Ced-4

Active�Ced-3

Other�proteases

Nucleases

Activation�cascade

(b) Death signal

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Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis

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Apoptosis can be triggered by

An extracellular death-signaling ligand
DNA damage in the nucleus
Protein misfolding in the endoplasmic reticulum

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Interference with apoptosis may contribute to some cancers

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2. Coordinating responses

Different kinds of cells have different collections of proteins
These different proteins allow cells to detect and respond to different signals

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Signaling�molecule

Receptor

Relay �molecules

Response 1

Cell A. Pathway leads�to a single response.

Response 2

Response 3

Response 4

Response 5

Activation�or inhibition

Cell B. Pathway branches,�leading to two responses.

Cell C. Cross-talk occurs�between two pathways.

Cell D. Different receptor�leads to a different�response.

Pathway branching and “cross-talk” further help the cell coordinate incoming signals

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Signaling�molecule

Receptor

Relay �molecules

Response 1

Cell A. Pathway leads�to a single response.

Response 2

Response 3

Response 4

Response 5

Activation�or inhibition

Cell B. Pathway branches,�leading to two responses.

Cell C. Cross-talk occurs�between two pathways.

Cell D. Different receptor�leads to a different�response.

Different cells can respond the the same ligand in different ways

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Receptor

Relay �molecules

Response 1

Cell A. Pathway leads�to a single response.

Response 2

Response 3

Response 4

Response 5

Activation�or inhibition

Cell B. Pathway branches,�leading to two responses.

Cell C. Cross-talk occurs�between two pathways.

Cell D. Different receptor�leads to a different�response.

For example:

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Signaling�molecule

Receptor

Plasma�membrane

Scaffolding�protein

Three�different�protein�kinases

3. Scaffolding proteins are large relay proteins to which other relay proteins are attached

Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway

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4. Termination of the Signal

Inactivation mechanisms are an essential aspect of cell signaling

If ligand concentration falls, fewer receptors will be bound
Unbound receptors revert to an inactive state

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Plasma membrane

EXTRACELLULAR�FLUID

CYTOPLASM

Reception

Transduction

Response

Receptor

Signaling�molecule

Activation�of cellular�response

Relay molecules in a signal transduction�pathway

3

2

1

III. Changes

Mutations in any domain of the receptor or in any component of the signaling pathway can affect the final response

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Reception

Transduction

Response

Receptor

Signaling�molecule

Activation�of cellular�response

Relay molecules in a signal transduction�pathway

3

2

1

Medications, toxins, other chemicals that change any part of the pathway may activate or inhibit the pathway

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What happens if the inhibitor is inhibited?

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IV. Feedback

Negative feedback regulates most metabolic pathways

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Positive Feedback - a change in a system causes even more change in the same direction. The result is a continuing spiral of change. (This amplifies the response)

+

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Feedback is different from control groups

Positive – a group with a known, expected result to ensure the experiment is functioning. The result of the control group must be known, and is not what was tested.
Negative - a group with one factor removed; expect no result as a comparison to the group that has that factor

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Vocab about the immune system

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Vocab about the immune system

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Vocab about Communication in Microbes

biofilm - microorganisms that stick to each other and often also to a surface.

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Vocab about Communication in Microbes

quorum sensing - the regulation of gene expression in response to fluctuations in cell-population density.

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Stem Cell

Undifferentiated cell that can become a specific cell type

Embryonic stem cells can differentiate into many other cell types.