Cell Communication and Signaling

How do cells communicate

Through a large variety of extracellular signals

Cells must __ signals that they receive from other cells to help __ their responses

interpret, coordinate

What does cellular communication involve, regarding signals

Involved converting signals from one form to another

What is process of converting signals from one form to another called

Signal transduction

What occurs in signal transduction

elicits a SPECIFIC cellular response which causes changes in gene expression, protein expression, morphological changes, etc.

How does typical communication between cells occur

the signaling cell produces a signal molecule that’s detected by target cell, which have receptor proteins that recognize + response to the signal molecule.

How does signal transduction begin

When receptor protein on target cell receives an incoming extracellular signal and converts it to an intracellular signal.

What do extracellular signal molecules do

stimulate a target cell by binding to its receptor proteins, including intracellular and cell-surface receptors

In what ways can extracellular signals act?

slowly or rapidly

What are 4 types of cell communication

endocrine (estrogen, insulin), paracrine (egf, bmp, wnt), neuronal (acetylcholine, GABA), contact-dependent (delta-notch)

Endocrine signaling

The most “public” style of communication, broadcasts a signal (hormones) throughout whole body through secretion into bloodstream (or plant’s sap)

What cells produce hormones

endocrine cells

Example of endocrine signaling + where they’re produced

Adrenaline: hormone produced by adrenal gland

Insulin: peptide hormone, produced by the b cells of the pancreas

What does the pituitary gland do

endocrine gland that produces multiple hormones regultating many different organs

What does excess growth hormone lead to

Acromegalia

What’s paracrine signaling

Its a local mediator and signal molecules regulating the inflammatory response work in this manner

What’s autocrine signaling

Cells secrete factors that they express receptors for and stimulate their own growth/survival (ex: cancer cells)

How are short range signals released

By neighboring cells that function locally

Whats EGF

epidermal growth factor: a protein that stimulates cell proliferation

Whats BMP

bone morphogenic protein, a protein that promotes differentiation

Whats WNT

Wingless and INt-1, a protein that stimulates cell proliferation

What’s neuronal signaling

Neuronal signals are transmitted electrically along a nerve cell axon. When this electrical signal reaches the nerve terminal, it causes the release of neurotransmitters onto adjacent arget cells (the process by which neurons communicate using electrical/chemical signals to transmit info thru nervous system)

Example of neuronal signaling

Acetylcholine (excitatory neurotransmitter at nerve-muscle synapses and CNS) and GABA (inhibitory neurotransmitter in CNS)

How is signal transmitted and what occurs after

Neurotransmitters are transmitted along axons to remote target cells. When action potentials reach the axon terminal, electrical signals are converted into chemical signals in the form of neurotransmitters. The neurotransmitters then diffuses across synaptic gap to reach membrane of target cells

What’s juxtacrine signaling/contact-dependent signaling

Cells make direct physical contact through signal molecules lodged in the plasma membrane of the signaling cell and receptor proteins embedded in the plasma membrane of the target cell (transmembrane protein signaling between two neighboring cells)

Example of juxtacrine signaling

in embryonic development, contact-dependent signaling allows adjacent cells to become more specialized to form different cell types

What is the notch receptor

a transcription factor (delta receptor)

What is delta and what does it do

membrane-bound signal protein; inhibits neighboring cells from becoming specialized in the same way as the signaling cell

What happens when delta binds to its receptor, notch

The receptor is cleaved. The released part of the cytosolic tail of notch migrates to the nucleus, where it activates Notch-response genes, such as genes that inhibit neuronal differentiation in fruit flies

How many signals are cells of multi-cellular organisms exposed to

hundreds

What determines whether or not cells response to the hundreds of signals they r exposed to

if the cells possess a receptor protein for that specific signal

Is the message the extracellular signal molecule

No, the message depends on how the target cell receives/interprets the signal

Example of same signal, different responses

Acetylcholine: induces different repsonses depending on cell type and receptor
In heart-pacemaker cell, causes decreased rate of firing
In salivary gland cell, causes secretion
In skeletal muscle cell, causes contraction

2 large categories of extracellular signals

(1) too large/too hydrophilic to cross membrane, (2) small enough and hydrophobic enough to diffuse across plasma membrane

What do large and/or hydrophilic molecules rely on to relay message across membrane

membrane receptors

What do small and/or hydrophobic molecules rely on to relay message across membrane

diffusion across plasma membrane or binding to intracellular enzymes/intracellular receptor proteins

Examples of cell-surface receptors and their signals

(a) growth factors (EGF) → EGFR or ErbBi

(b) peptide hormones (insulin) → insulin receptor (IR)© neurotransmitter (acetylcholine) → nicotinic acetylcholine receptor

Examples of intracellular receptors and their signals

(a) steroid hormones (Estrogen or cortisol) → estrogen-cytoplasmic receptor and cortisol-cytoplasimc receptor

What are two options that extracellular signal molecules bind to

cell-surface receptor or intracellular receptor

What is cortisol receptor + process of cortisol binding

receptor located inside cell that is translocated to the nucleus → cortisol binds to nucleaer receptor protein after conformation change that activates it, the activated complex moves into nucleus and binds to regulatory region of target gene and activates transcription

Whats combinatorial signaling

Process where multiple signaling pathways interact to produce a more complex or finely-tuned cellular response

Questions regarding combinatorial signaling

(1) Cell in our bodies can be exposed to many pos and neg signals: how does the cell coordinate appropriate resposnes and what happens if they dont

(2) Some signals function in a concentration-dependent manner: how do concentration differences elicit different responses

(3) responses to signals require the appropriate receptors that are expressed in a highly cell-type specific manner: how does cell know to express correct receptors?

How do extracelular signals activate intracellular signaling to change the behavior of the cell

1/2) The receptor protein performs the 1st signal transduction step: It binds the extracellular signal (primary messenger).

3) The receptor generates new intracellular signals (secondary messengers), in which the message is passed “downstream” from one molecule to another.

4) Until an enzyme/protein/regulator is kicked into action.

5) The final outcome is called the response of the cell.

What crucial functions can intracellular signaling pathways perform

1) Relay the signal onward.

2) Amplify the signal received, make it stronger so that only a few intracellular signaling molecules can evoke a large intracellular response.

3) Receive signals from multiple intracellular signaling pathways and integrate them.

4) Distribute the signal to more than one signaling pathway or effector protein.

5) Engage in feedback, modulating the response of the signal.

How is signal transduction performed by phosphorylation/dephosphorylation

Serine threonine kinases (p-Ser and p-Thr) and tyrosine kinases (p-Tyr): Signal entrance causes dephosphorylation of ATP through protein kinase which phosphorylates protein, then when the phosphate is dephosphorylated, the protein turns off

How can signal transduction be done through GTP hydrolysis and exchange

Signal entrance causes GTP binding to protein which turns protein on. The signal leaves, and GTP hydrolysis occurs so GDP binds to protein and it’s turned off

What’s GEF

guanine nucleotide exchange factor

What’s GAP

GTPase activating protein

Inactive versus active monomeric GTPase and how that process works

GEF and GTP binding turn on monomeric GTPase, and then GAP dephosphorylates it, which leads to GDP binding and an inactive monomeric GTPase

What do kinases do

phosphorylation of one protein activates phosphorylation of the next

How do GTP-binding proteins work

activation depends onw hether or not GTP or GDP is bound

What do molecular switch allow signals to do

they can switch between inactive and active states; so once activated, these proteins can turn on other proteins in the singaling pathway and they persist until another switch turns them off

3 main classes of cell surface receptors

ion channel-coupled, g protein-coupled, enzyme-coupled receptors

How do ion-channel-coupled receptors work

closed channel and then when signal molecules bind, channel opens and ions can enter cytosol

Barbiturates and benzodiazepines (valium and ambien), their normal signal, receptor action, and effect

normal signal: GABA
receptor action: stimulate GABA-activated ion-channel-coupled receptors

effect: relief of anxiety; sedation

Nicotine, their normal signal, receptor action, and effect

normal signal: acetylcholine
receptor action: stimulates acetylcholine-activated ion-channel-coupled receptors

effect: constriction of blood vessels; elevation of blood pressure

Morphine/heroin: their normal signal, receptor action, and effect

normal signal: endorphins/enkephalins
receptor action: stimulates G-protein-coupled opiate receptors

effect: analgesia (relief of pain); euphoria

Curare: their normal signal, receptor action, and effect

normal signal: acetylcholine
receptor action: blocks acetylcholine-activated ion-channel-coupled receptors

effect: blockage of neuromuscular transmission, resulting in paralysis

Strychnine: their normal signal, receptor action, and effect

normal signal: glycine
receptor action: blocks glysine-activated ion-channel-coupled receptors

effect: blockage of inhibitory synapses in the spinal cord and brain, resulting in seizures/muscle spasm

Capsaicin: their normal signal, receptor action, and effect

normal signal: heat
receptor action: stimulates temperature-sensitive ion-channel-coupled receptors

effect: painful, burning sensation; prolonged exposure can paradoxically lead to pain relief

Menthol: their normal signal, receptor action, and effect

normal signal: cold
receptor action: stimulates temperature-sensitive ion-channel-coupled receptors

effect: in moderate amounts, a cool sensation; at higher doses, can cause burning pain

What do G-protein coupled receptors do

Activates membrane-bound, trimeric GTPbinding proteins (G proteins), which then activate either an enzyme or an ion channel in the plasma membrane.

What are GPCRs composed on

a single polypeptide chain that is a seven-pass transmembrane receptor protein.

What happens when GPCR is bound to a signal molecules

the receptor protein undergoes a conformational change that enables it to activate a G protein on the cytosolic side.

What do different G proteins do

each is specific for a set of receptors and target enzymes or ion channels.

What are each G protein composed of

α, β, and γ subunits

What are G protein subunits tethered to

plasma membrane by short lipid tails

What occurs to a subunit of G protein in the unstimulated state

the α subunit has GDP bound, and the G protein is inactive

What hapens to a subunit when an extracellular ligand binds to the receptor

the receptor activates the G protein by causing the α subunit to release GDP and exchange it for GTP

What is the role of a subunit in G protein

α subunit has intrinsic GTPase activity, and ultimately, will hydrolyze the GTP back to

GDP returning the G protein back to its inactive state (activation → hydrolysis → inactive)

How can GCPRs activate membrane bound enzymes

Enzymes activated by G proteins increase the concentrations of small intracellular signaling molecules, which diffuse to act on intracellular signaling proteins

How does Adneylyl cyclase do

produces cyclic AMP by removing 2 phosphate groups from ATP and forming a cyclic structure

What is cyclic AMP (cAMP)

secondary messenger

Whats PKS and what does activated PKA do

protein kinase A, activated PKA regulates function of glycogen phosphorylase

How does process of GPCR → adenylate cyclase → cAMP work

cyclic AMP activates PKA which enter nucleus through nuclear pore. PKA then phosphorylates/activates transcription regulator which leads to transcription of target gene

How does process of GPCRs → Phospholipase C → IP3 and DAG work

A signal molecule binds to a GPCR, activating it and leading to an activated G protein, which in turn activates phospholipase C.

Then, inositol phospholipid was converted into diacylglycerol and inositol 1,4,5-triphosphate.

Inositol 1, 4, 5-triphosphate binds to the Ca2+ channel on the ER, which leads to the release of Ca2+, which binds to PKC and diacylglycerol to activate PKC A

What are enzyme-coupled receptors

they are transmembrane proteins that display their ligand-binding domains on the outer surface of the plasma membrane.

How does cytoplasmic domain of enzyme-coupled receptor act

Either as enzyme itself or forms a complex with another protein that acts as an enzyme

What do enzyme-coupled receptors respond to + what do they do

respond to extracellular signal proteins (growth factors); they regulate cell growth, proliferation, differentiation, and survival (typically slow response)

Example of enzyme-coupled receptor function

they mediate and direct rapid reconfiguration of cytoskeleton and control cell shape/movement

What are RTKs

A large class of enzyme-coupled receptors called enzyme-linked receptor tyrosine kinases

What do RTKs contain

a cytoplasmic domain that phosphorylated specific tyrosines on selected intracellular proteins

What does binding of signal molecule to extracellular domain of RTK do

Causes two receptors to associate into a dimer

What does dimerization do

Activates RTK kinase activity, enabling them to phosphorylate their tyrosines. Each phosphorylated tyrosine serves as a specific binding site for a different intracellular signaling protein, which relays the signal to the cytosolic region

What is Ras

Rat sarcoma: a small GTP-binding protein that is bound by a lipid tail to the cytoplasmic face of the plasma membrane. It’s a member of a large family of monomeric GTPases

What are monomeric GTPases

Resemble the a subunit of a G protein and acts as a molecular switch

What does adaptor protein do

docks on specific phosphotyrosine on the activated RTK and recruits Ras-GED stimulating Ras to exchange its bound GDP for GTP, which leads to onward transmission of the signal

What do 30% of human cancers contain

activating mutations in Ras genes

What does active Ras do

promotes activation of phosphorylation cascade

What’s a phosphorylation cascade

series of serine/threonine protein kinases

What does Ras active, and what does that thing do

MAPK signaling molecule (mitogen activated protein kinase), which phosphorylates various downstream signaling pathways that control cell proliferation

How does process from IFG → PI 3-kinase → Akt work

IGF acts through RTKs, which in turn activates the phosphoinositide 3-kinase (Pi 3-kinase) which then phosphorylates membrane-associated inositol phospholipid, which recruits a protein kinase (Akt) that’s activated by protein kinase 1 and 2

What is IGF

Insulin-like growth factor, is important for cell survival and proliferation and acts through RTKs

What does activation of Akt promote

cell survival by inhibition of apoptosis: Bad is bound to inactive Bcl2 and phosphorylation of Bad releases active Bcl as a result of active Akt/survival signal. This leads to inactivated Bad and active Bcl2

How does IFG → PI 3-kinase → Akt → Tor process lead to cell grwoth

PI-3-kinase-Akt signaling pathway also Akt indirectly activates Tor by phosphorylation and

inhibiting a protein that helps to keep Tor inactive.

What is Tor

a serine/threonine kinase that stimulates protein synthesis and inhibits protein degradation

What is disruption of Tor signaling associated with

multiple diseases from cancer to neurodegeneration

What do mutant proteins do

help determine exactly where an intracellular signaling molecule binds

What occurs to tyrosines (Y2 anord Y3) in point mutations and what does that do ********redo

replaced by an alanine which means the mutant receptor no longer binds to one of the intracellular signaling proteins (ex: if Y2 changed to alanine, Y3 can’t bind), which can then determine the effect on the cell’s response to the signal

How can study genetic analyses through signaling pathways

Ex: if a pathway involved Ras, protein x, and protein y,
(a) In a cell with mutant protein X, if the introduction of overactive Ras restores signaling, you can conclude that Ras acts downstream of protein X

(b) In a cell with mutant protein Y, if the introduction of overactive Ras does nothing, you can conclude that protein Y acts downstream of Ras

Ex 2: You can deduce the order of proteins in a pathway