SIGNAL TRANSDUCTION FULL DECK

Cell signaling (multicellular)

• Cells require constant signaling from their environment, other cells, and their own interior

The diagram shows different examples of cells getting various combinations of signals, which enable them to perform specific functions.

1. Cell 1 is getting signals from signals A,B,C to tell it to survive

2. Cell 2 is getting signals from A, B, C AND D, E, which tells it to divide

3. Cell 3 is getting signals from A, B, C AND F, G telling it to mature

4. Cell 4 has no signals which means it should undergo apoptosis

unicellular cell communication

Single-celled organisms can communicate with each other

yeast cell communication

• They communicate by secreting soluble factors on each other. also known as mating factors

• The Saccharomyces cerevisiae yeast has two different factor types, the “a” type and the “α” type

• The “a” type and “α” type yeast can only mate with each other, so they send each other the mating factors, and can only bind to each other’s receptors 

Quorum sensing

• Prokaryotes, single-celled organisms, can use this to cell signal

• a form of bacterial communication where cells release signal molecules to sense their population density 

local signaling

whens cells communicate with nearby cells, or with cells in direct contact with them.

Direct contact local signaling

Gap junctions in animal cells, plasmodesmata in plant cells, and Transmembrane proteins for cell-to-cell recognition all allow for direct local signaling

Plasmodesmata

channels in land plant and algal cell walls that connect the cytoplasm of neighboring cells, allowing for direct transport and communication of molecules like sugars, ions, proteins, and RNA

gap junctions

Protein channels in animal cells that connect the cytoplasm of adjacent cells, allowing direct passage of ions, small metabolites, and signaling molecules without entering the extracellular space

cell-to-cell interactions: Transmembrane proteins

Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane

Non direct contact local signaling

paracrine signaling and Autocrine signaling

paracrine signaling

• Animal cells may use secreted messenger molecules (molecules travel short distances) to communicate with the target cell

• The target cell must have a specific receptor for that messenger molecule 

synaptic signaling

a specific type of paracrine signaling. An axon will extend to target cell, and release neurotransmitters.

Autocrine signaling

the secreting cell will send a signal, and it binds back on itself on its own receptor

long distance signaling

endocrine signaling

endocrine signaling

the secreting cell will send signals into the blood stream and travel down the blood vessel to the target cell

signaling molecules

can be either polar or nonpolar. 

• Nonpolar molecules easily travel through the plasma membrane. The signal molecule will enter the target cell and bind to a receptor inside the target cell. when the receptor binds to the signal, the receptor will go through a. conformational change (steroids are generally non-polar, e.g., cortisol)

• polar signal molecules will find their receptor embedded in the plasma membrane (polypeptides and amino acids generally polar, e.g., secretin and epinephrine, respectively)

ligand

signal molecule

4 main types of receptors

1. Intracellular receptors

2. ion channel receptors

3. G-protein-linked receptor

4. Protein kinase (enzyme-linked) receptors

Intracellular receptors

• located in the cytoplasm and nucleus

• binds to nonpolar signal molecules

• is often a transcription factor (After the ligand binds to the receptor, the receptor will go through a conformational change, which allows the ligand+receptor unit to change location, into the nucleus to aid in transcription)

Ion channel receptors

• transmembrane receptor

• When a ligand binds to the receptor, a conformational change causes the channel's "gate" to open, allowing specific ions (like Na⁺, K⁺, Ca²⁺, or Cl⁻) to flow across the cell membrane

• “ligand-gated ion channel” (the presence of a ligand determines if the channel is open or closed)

Neuron signaling is an example 

G- protein linked receptor

a receptor bound to a G protein

Protein kinase receptors

• kinase is an an enzyme that puts a phosphate group on something

• Upon binding to a ligand, the kinase receptor will transport phosphate groups to proteins

signal transduction pathway 

an external signal, such as a hormone or neurotransmitter, triggering a series of molecular events, that forms the cells response to the signal.

basically a ligand binds to surface receptor→intracellular events occurs→these events trigger the the cellular response 

Signal transduction parts

1. Reception- the target cell detects that the signaling molecule has bound to the receptor

2. transduction- signaling/relay proteins work as intermediates, activating and changing, and communicating with one another, to tell the cell that the binding has occurred

3. response- the final response (such as a change of enzyme, alteration of gene expression, or change in cell shape to move somewhere else)

multiple responses

there are many different response paths that a binding can cause.

• One pathway can fork off into two different responses

• 2 different signaling molecules pathways can communicate, and create a unique response

Reception

1. After the ligand binds to the surface receptor, the target cell detects that this binding has occurred

2. The receptor molecule (ligand + receptor) will go through a conformational change

transduction

the relay molecules will interact with each other one by one

G protein coupled receptor

• transmembrane receptors that get coupled with G proteins

• Usually, the polypeptide chain of this receptor folds on itself 7 times through the membrane

• largest family of cell surface receptors 

G proteins

• G protein bound to GDP is off (inactive)

• G protein bound to GTP is on (active)

G protein receptor process

• When a ligand (epenephrin is a common ligand for this process) binds to the receptor, it goes through a conformational change, which allows the receptor to have contact with a G protein.

• The contact will allow the G protein to drop its GDP and gain GTP.

• The G protein will move to an enzyme, activating the enzyme.

Adenylyl cyclase

• one enzyme that the G protein can bind to

• this enzyme can generate many '“second messengers'“ after being activated

second messengers

small non-protein molecules or ions that are water-soluble. They spread throughout the cell very quickly by diffusion. It can bring its information to a protein inside the cell.

cAMP molecules and calcium ions are common secondary messengers

The first ligand that binds to the G protein receptor (e.g., epinephrine) is a first messenger 

Cyclic AMP (cAMP)

• one of the most commonly used second messengers

• The Adenylyl cyclase enzyme will chop 2 phosphates from an ATP (the 2 phosphates will just leave)

• The remaining phosphate connects to the 5’ and 3’ carbons on the ribose sugar of the ATP, creating cAMP, aka the second messenger

• Another enzyme called phosphodiesterase will further break down cAMP, creating AMP

Protein kinase A

• One of the main targets of the cAMP secondary messenger

• cAMP binding will allow protein kinase A to activate

• When protein kinase A gets activated, it phosphorylates other proteins/molecules

phosphorylation cascade

A kinase will get activated and phosphorylate other kinases, which will trigger that kinase to get activated and phosphorylate another kinase. This cycle continues, however many times, until the final kinase phosphorates an inactive protein, creating an active protein that can create a cellular response

Full cycle of Epeniphrine binding to G protein receptor

1. epinephrine binds to the G protein receptor, creating a conformational change

2. The conformational change triggers the receptor to make contact with a G protein

3. The contact will make the G protein drop its GDP. and pick up GTP, which also activates the G protein

4. The activated G protein will go to an adenylyl cyclase enzyme, activating the adenylyl cyclase 

5. Adenylyl cyclase, once activated, takes ATP and turns it into cAMP (secondary messenger)

6. cAMP binds to inactive protein kinase A and activates it

7. A phosphorylation cascade occurs, and the protein kinase A will phosphorylate phosphorylase kinase, which activates it, which then phosphorylates an inactive glycogen phosphorylase, which activates it, and the active glycogen phosphorylase will take glycogen and break it down and eventually release glucose from the cell.

8. At the same time, glycogen synthase gets inactivated to stop the production of glycogen

result of phosphorylation cascades

Phosphorylation cascades don’t just have to end with breaking molecules down.

They can also lead to the final kinase entering the nucleus and alter a transcription factor

phosphorylation cascade and transcription factors

• The kinase series gets activated

• the last kinase in the cascade enters the nucleus and binds to. an inactive transcription factor, creating an active transcription factor 

• The activated transcription factor binds to a specific DNA sequence and activates gene expression

Amplification

A single binding can cause amplification, which is when a small initial stimulus leads to a large and significant cellular response

Example: 1 epinephrin binding can create around 100 active G proteins that diffuse out and activate 100 enzymes, which will produce 1000 cAMP, which will bind to 1000 pK-A, which will phosphorylate 100000 phosphorylase kinase, which will phosphorolyze 1000000 glycogen phosphorolase, which will break down and release 100000000 glucose molecules out of the cell.

reversable modifications

stop a signal after its serves its purpose, allowing it to return to its resting state. 

protein phosphatase is an enzyme that assists in reversible modifications

protein phosphatase

enzymes that work to cut off added phosphate group in phosphorylation. This deactivates the proteins and stops its role in the phosphorylation cascade 

Calcium ion as a second messenger

• Ca+ is small, water-soluble, and freely diffusible, making it a good second messenger

• There is a low concentration of it in the cytosol because Ca+ gets pumped out of the cell, as well as pumped inside storage organelles like the mitochondria or ER

• When Ca+ concentration DOES rise in cytosol, any protein dependent on calcium concentration can become activated

• Protein Kinase C is a protein responsive to calcium concentration

Calcium as secondary messenger

many pathways use calcium instead of cAMP or in addition to cAMP, as a secondary messenger

• Ca+ is small, water-soluble, and freely diffusible, making it a good second messenger

• There is a low concentration of it in the cytosol because Ca+ gets pumped out of the cell, as well as pumped inside storage organelles like the mitochondria or ER

• When Ca+ concentration DOES rise in cytosol, any protein dependent on calcium concentration can become activated

• Protein Kinase C is a protein responsive to calcium concentration

Where is Ca2+ located in the cell?

• mitochondria or ER until the channel opens

phospholipase C

• an enzyme linked to a pathway involving Ca ions.

• can cut phospholipids

• After first messenger binds to G protein receptor, the G protein will interact with the receptor and drop its GDP and gain GTP, which activates it to be mobile, and attach to phospholipase C.

Full Ca pathway

1. signal molecule attaches to receptor

2. receptor goes through a conformational change and will interact with G protein

3. interaction with G protein causes it to lose its GDP nad gain GTP, causing it to be mobile and travel to phospholipase C

4. phospholipase C activates, cuts PIP2 molecule creating IP3 molecule (the second messenger)

5. IP3 diffuses to a gated calcium channel and binds to it. the binding opens the channel

6. The channel opening allows the Ca2+ ions inside the ER to travel out to the cytosol

7. The ions can bind to many different protein types, and depending on what it bind to cause a specific cellular response

protein Kinase receptor

• class of cell surface receptors that play a crucial role in signal transduction pathways

• resposible for protein phosphorylation

• a specific one we will focus on is the receptor tyrosine kinases (RTK)

Receptor tyrosine kinase (RTK) structure

one RTK monomer has

• a binding site that the ligand can bind to

• a side in the cytoplasm that has RTK proteins on them to help with its enzymatic fuction

• The side in the cytoplasm has tyrosine proteins on them

RTK binding 

1. Either 2 signal molecules can bind to 2 independent RTK molecules, causing them to combine and turn into a dimer, OR 1 signal molecule can bring the two RTK molecules together and bind to both at the same time

receptor tyrosine kinases (RTK) process

• Their unactivated state is independent, but when activated, it combines with another RTK receptor

• The dimerization activates the molecule and goes through autophosphorylation, which means the two monomers put phosphate groups on each other’s tyrosine proteins

• the phosphates come from ATP, so at the end of the auto-phosphorylation, it converts its used ATP to ADP

• Now in its fully phosphorylated form, the dimer can bind with relay proteins

• the binding of the relay prtiens is the beginning of the tranduction

Scafollding peoteins

• multiple protein kinases can combine together with a scaffolding protein

• this increases the signal transduction efficiency because multiple proteins are already groped together and can bind to a receptor together 

Termination of Signals

After a signaling molecule sends a signal which brings about a response, and then it needs a way to end the signal.

→ They can use

• reversible binding

• turning off enzymes

reversible binding

1. The two molecules (ligand and receptor) will join together and come apart

(The signaling molecule diffuses away from the receptor)

2. After inactivating all the proteins affected by the initial binding inactivates as well

3. for example an activated G protein with a GTP will turn off by hydrolyzing the GTP and gaining GDP

GTPase

when a G protein can hydrolyze its bound GTP (turning off on its own)

whena g protein is not a GTPase, it will get assistance from an enzyme to shut off

Termanation of signal- what happens to the ezyme

• the protein will diffuse away from the enzyme, making it inactive again

• all the molecules made by the enzyme gets destroyed

phosphodiesterase

• An enzyme that destroys all the second messengers created by the enzyme after the enzyme is inactivated

What if the Termination of a signal does not occur? (example)

• Vibrio cholerae (cholera) produces a toxin that modifies a G protein so its stuck in active form

• this causes the protein to continually produce cAMP causing intestinal cells to secrete large amounts of salt into the intenstines

• water follows by osmoses

• an untreated person will lose salt and water and can die

how are cells different from eachother?

• Cells are different from each other because they have different collections of proteins

• They have different proteins within them because they have different genes being expressed

specificity of cell signaling

the arrival of the same signaling molecule in different cell types can bring about different effect

the different effects can be becuase

1. the proteins within the cells are different

2. a cross talk between two signal molecules binding can cause a new pathway

3. the signal molecule binds to a different receptor

Why does the Same signal-molecule/receptor binding bring different pathways for different cell types?

The proteins in the cells are different.

Cross-talk

• a cross-talk is when two different signaling molecules bind to their receptors, and the result of the two binds occuring leads to a new path

• a cross-talk is another reason why different cells can have different responces to the same signal molecule binding

different receptor

• different receptors will communicate with different relay protein

acetycholine binding with different cells

A. heart pacemaker cell- binds to G protein receptor cell. Upon binding it decreases the rate of firing

B. salivary gland cell- binds to G protein receptor cell. Upon binding, the cell secretes saliva

C. skeletal muscle cell- binds to an ion channel-coupled receptor. upon binding, it allows for contraction of the muscle

epinephrin binding to different cells

A. liver cell- binds to its beta receptor. upon binding breaks down glycogen and releases glucose

B. skeletal muscle blood vessel- binds to beta receptor. Upon binding, the vessel dilates

epinephrin binding to same cell different receptors

Receptors in the blood vessel

A. Beta receptor- upon binding, the vessel dilates

B. Alpha receptor- upon binding, the vessel contracts

Signal for apoptosis (example)

for soil worm caenorhabditis elegans

• apoptosis is triggered by signals that activate a cascade of “suicide” proteins

• when death signal is received, an apoptosis inhibiting protein (Ced-9) is inactivating allowing for the caspase “suicide” proteins to promote apoptosis

Ced-9 protein

protein inhibiting apoptosis. usually activated unless inactivated

Capases

proteins that carry out apoptosis

Apoptosis pathways and signals triggering them

• humans have several different pathways to carry out apoptosis

• apoptosis can be triggered by signals outside the cell or inside

• internal signals include- DNA damage, protein misfolding

apoptosis steps

1. initial- sudden release of cytochrome c from the mitochondria into cytosol

2. second- the lipid asymetry of plasma membrane breaks down (phosphatital serine is found in the cytosol, but during apoptosis it is found outside the cell and other cells such as macrophages can consume the content)

3. final- the plasma membrane becomes permeable to small molecules