UMKC SOD 2016 Cell Biology Lecture 2

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What is the definition of signal transduction?

Process by which a signal (usually extracellular) causes a cellular response

How does a signal transduction pathway work?

Pathway of proteins and small molecules that transmit signal in cell causing an intracellular response

What are some important processes that ST pathways can control?

Survival/Death
Proliferation
Differentiation

There are 4 main components of a ST pathway. Name them.

1. Ligand - protein or small molecule that binds receptor
2. Receptor - cellular protein usually present on cell surface
3. Intracellular signaling protein (ISP)/2nd Messengers - transmit the signal
4. Targets - often in cellular components distant from the receptor, expression changes as a result of signal

How many ISPs/2nd messengers do you typically see per pathway?

5-20

What is an endocrine signal?

Ex. Adrenal gland, pancreas, liver

Export hormones, growth factors, and other signaling molecules directly into bloodstream. These ligands then signal other tissues

Which type of signal is a ligand exported from cells and diffuse to surround tissue?

Paracrine

Ex. Morphogens, Neural signals, autocrine signals

What is a cell-cell contact signal?

Ligand on the surface of one cell that binds and activates receptor of the neighboring cell

What are some examples of protein ligands?

Delta, growth factors, insulin (peptide)

What are some examples of small molecule ligands?

Ach, Serotonin, Adrenaline, steroids, nitric oxide

True or False. There are two types of receptors - cell surface receptors and intracellular receptors.

True

What type of proteins are cell surface receptors?

Transmembrane proteins

How do cell surface receptors work?

Extracellular domain of receptor binds specific ligand causing conformational change in intracellular domain of the receptor, passing the signal inside the cell to other proteins

Which type of receptors are steroid hormone receptors, NO binding proteins that bind molecules that can transverse the plasma membrane?

Intracellular receptors

What is an example of an ISP?

G protein

Describe the process of steroid receptor as an intracellular receptor.

Cortisol passes through the plasma membrane --> They bind nuclear receptor protein which causes a conformational change in that protein --> Activated receptor/cortisol complex moves into nucleus --> Complex binds to regulatory region of a target gene and activates transcription

What is a specific example of a steroid receptor as an intracellular receptor?

Glucocoticoid receptor, a transcriptional activator that regulates tyrosine amino transferase (TAT) gene in response to exercise

Describe the dual extra/intracellular signaling of endothelial cells to muscle cells.

Ach release from pre synaptic terminal and binds to extracellular receptor on endothelial cell --> Causes NO to diffuse across the membrane and into smooth muscle where is binds to a target protein --> NO plus bound protein complex leads to relaxation of smooth muscle

Describe how vascular smooth muscle relaxes.

NO binds to and activates gunaylyl cycles stimulating the formation of cyclic GMP from GTP

True or False. Receptors and ISPs are ON/OFF switches.

True

What are the three most common types of ST pathways?

1. Ion channel coupled receptor pathway
2. G protein coupled receptor pathway
3. Enzyme linked receptor pathway

How are the three different pathway types defined?

By the RECEPTOR

Describe the action of an Ion Channel Coupled Receptor.

Ach accumulates (or other ligand) in the extracellular space --> This signal ligand binds to receptors and causes a conformational change, opening up the receptor and allowing ions to pass to the cytosol

How does the receptor of a G protein work?

There is an extracellular ligand binding location and an intracellular binding location that becomes activated upon ligand binding to the external receptor

Describe the action of a general GPCR.

Signal molecule binds to the extracellular component of the GPCR --> This small conformational change causes the GPCR to associated with the trimeric G protein that is bound to the PM --> As soon as the alpha subunit of the G protein associated with the receptor it exchanges GDP for GTP and then becomes activated along with the beta/gamma subunit

Describe how a GPCR pathway can open a K+ channel on the plasma membrane.

Ach binds to the extracellular GPCR and causes a change in the intracellular AA sequence when causes the trimeric G protein to associate (Exchange GDP for GTP) and then dissociate into alpha and beta/gamma subunits --> Beta/gamma subunit associates with the K+ channel and opens it, allowing K+ to leave the cell --> Phosphatase acts to cleave a phosphate from GTP back to GDP, causing the alpha and beta/gamma subunits to re-associate and inactivate

Describe one of the pathways of the GPCR branching.

Adrenaline binds to extracellular GPCR and activates the adrenergic receptor --> This activates protein subunit Gs which in turn activates adenylyl cyclase --> Adenylyl cyclase can then convert ATP into cyclic AMP --> cyclic AMP activates inactive PKA --> Active PKA phosphorylates an inactive phosphorylase kinase which can then in turn activate an inactive glycogen phosphorylase via phosphorylation --> This active glycogen phosphorylase leads to glycogen breakdown and the production of glucose

In that branching pathway, how is cyclic AMP inactivated into AMP?

Phosphodiesterase

True or False. PKA would be considered a transcription factor.

True

When adenylyl cyclase converts ATP into cyclic AMP what is this an example of?

Second messenger amplification

Describe another example of GPCR branching.

Signal molecule binds to extracellular GPCR causing trimeric G protein to associate, exchange GDP for GTP and become activated --> The activated alpha subunit activate PLC which cleaves inositiol phospholipid --> Diacylglycerol remains associated with the membrane while IP3 travels through the cell to bind to calcium channels on the ER --> Upon binding of IP3, calcium channels of the ER open and release Calcium --> Calcium associated with the diacylglycerol/PKC complex on the plasma membrane and activates PKC

What are examples of second messengers in this pathway?

Ca2+, IP3, diacylglycerol

In pathway branching what do the following effect: GPCR, Alpha subunit of GP, PKA, PLC

GPCR - beta/gamma and alpha subunits of trimeric G protein

Alpha subunit of GP - adenyl cyclase, PLC

PKA - phosphorylates/activate both TFs and metabolic enzymes

PLC - IP3 targets and DAG (diacylglycerol) targets

What are some examples of second messengers in the cell?

Ca2+, cAMP, IP3, cGMP, PIP

What are second messengers capable of greatly amplifying the signal during signal transduction?

Because only one molecule of enzyme can generate MANY molecules of 2nd messenger

How come second messengers are critical in pathway branching?

Because a given second messenger can activate more than one enzyme

Describe how trimeric G proteins utilize an "ON-OFF switch".

Activated alpha subunit binds a target (adenyl cyclase) --> Hydrolysis of the bound GTP to GDP + P inactivates the alpha subunit and causes dissociation from the target --> This also causes the alpha subunit to re-associated with the beta/gamma subunit to reform the trimeric G protein

Describe the GPRC ON-OFF switch - desensitization to light in rhodopsin

Hyper activated rhodopsin is phosphorylated by GRK kinase on the cytosolic side --> Phosphorylated rhodopsin binds a protein called arresting --> Arrestin binding prevent trimeric G protein from binding rhodopsin and targets receptor internalization into endosomes --> Endosomes either target rhodopsin to lysosome, where rhodopsin is destroyed or recycles inactive rhodopsin to PM

Describe the enzyme-linked receptor ST pathway.

Inactive receptor tyrosine kinases are not associated on the plasma membrane --> Signal molecule binds and causes dimerization of the RTK --> Tyrosine kinase domains on the receptors phosphorylate tyrosine residues to create active RTK --> As a result, intracellular signaling proteins can bind to phosphorylated tyrosine residues and rely signal to proteins in the cell's interior

What are 3 causes of insufficient bone size?

Periodontal disease/Tooth Gum disease
Removal of Tumor/Cyst
Following tooth extraction

What is an allograft?

Bone/Tissue transplant from the same species but from a different individual (ex. Human A to Human B)

What are some of the growth factors used to stimulate/incorporate a graft?

Human recombinant PDGF
Human recombinant Bone morphogenic protein
Plasma rich in growth factor (PRGF) - mix of growth factors isolated from patient's blood plasma

What ion triggers the release of GFs from platelet cells and subsequent polymerization of fibronectin into a fibrin network gel?

Ca2+

Besides grafting, what are other uses of growth factors in dentistry?

1. Preventing alveolitis (dry socket) after tooth extraction
2. Periodontal surgery, stimulates healing
3. Soft tissue surgery with alloplastic or host grafts

In all uses of growth factors of dentistry, how were growth factors shown to be effective?

Speed recovery, Reduce pain, reduce edema

Describe the downstream pathway of RTK.

RTKs dimerize and tyrosine kinase domains phosphorylate tyrosine residues --> Adaptor protein binds to an RTK which then binds to Ras activating protein which is a GEF --> The GEF exchanges GDP for GTP on inactive Ras protein --> Replacement with GTP activates Ras protein which activates MAP-KKK --> MAP-KKK hydrolyzes ATP into ADP + P and P binds and activates MAP-KK --> This same process occurs as MAP-K is activated --> MAP-K can then phosphorylate proteins and gene regulatory proteins to effect protein activity and gene expression

Describe two branches of the RTK pathway.

Survival signal binds to RTK and causes dimerization and subsequent phosphorylation of tyrosine residues --> Phosphorylated tyrosine activates PI3 Kinase which then phosphorylates IP2 and that become PIP --> PIP can activate PLC (example of integration, PLC can also be activated by GPCR pathway) --> PIP also activates and binds Protein Kinase 1 which along which protein kinase 1 phosphorylates and activates Akt --> Activated Akt relays cell signals which causes cell survival and increased cell size

How does the signaling by phorphorylation on-off switch work from the RTK pathway?

Kinase is Off --> Signal occurs and ATP is hydrolyzed into ADP + P, P binds to inactive kinase which becomes activated until it is inactivated by a phosphatase

What uses the signaling by phosphorylation method?

MAPK, MAPKK, MAPKKK, phosphorylase kinase, Akt

How does signaling by GTP binding protein work?

GDP bound to inactive kinase --> GEF exchanges GDP for GTP and the inactive kinase becomes active --> GAP (GTPase) then cleaves the phosphate and the kinase again becomes inactive

What uses the signaling by GTP binding protein method?

Ras

How do we turn switches "off"?

1. Destroy or inactivate (receptors internalized, cAMP turnover, arrestin binds rhodopsin)
2. Switch to OFF state (GAPs, kinases, pho sphatases)
3. Some components spontaneously revert to inactive state (Once receptor is no longer activated) - ex. beta/gamma reassociates with G alpha

Example of signal integration (G-protein)

GPCR binds ligand --> Activate G protein --> Adenylyl cyclase --> Cyclic AMP --> PKA --> Gene regulation/Protein expression

Example of signal integration (G-protein)

G protein --> PLC --> IP3 --> Ca2+ --> Calmodulin --> CaM kinase --> Gene regulation/Protein expression

Example of signal integration (PLC)

G protein --> PLC --> IP3 --> Ca2+ --> Calmodulin --> Cam Kinase --> Gene regulation/protein expression

Example of signal integration (PLC)

RTK --> PLC --> diacyglycerol --> PKC --> Gene regulation/protein expression

Example of signal integration (Ca2+)

Ca2+ --> Calmodulin --> Cam Kinase --> Gene regulation/protein expression

Example of signal integration (Ca2+)

Ca2+ --> PKC --> Gene regulation/protein expression

How does one mechanism of signal integration occur?

Protein A and Protein B each have ligands bind on the PM, they each relay signals that phosphorylate the same protein subunit and then relay the signal onward

How does another mechanism of signal transduction occur?

Protein A and Protein B each have ligands bind on the PM, they each relay signals that phosphorylate different proteins. Once phosphorylated, these proteins dimerize and relay the signal onward

What are examples of ways in which we have tested that ST pathways work?

1. Control ligand addition
2. Change expression/activity of ONE component and measure expression/activity of pathway components or response
3. Disrupt expression of TWO known components and measure expression/activity of other pathway components or response

What happens when Ras is deemed constitutively active?

Ras cannot hydrolyze GTP to GDP and thus there is continuous transmission of signal along the pathway, even in the ABSENCE of an extracellular signal molecule

How does normal signaling of Ras work?

Signal molecule binds to RTK and causes dimerization and subsequent phosphorylating of tyrosine residues from the tyrosine kinase domain --> An adaptor protein and kinase protein are activated by the phosphorylated tyrosine residues on RTK and these cause the exchange of GDP for GTP and subsequent activation of Ras which then activates another protein and causes downstream signaling

What happens when there is a mutation in the protein that associated with the phosphorylated RTK?

Despite phosphorylation of tyrosine residues following dimerization of the RTKs, protein X (typically a kinase) cannot interact and thus cannot serve as a GEF to exchange GDP for GTP on Ras. Ras remains inactive and there is no downstream signaling

If Ras is constitutive does it matter that the protein kinase that associates with the RTK is mutated?

No, the constitutively active Ras can still affect downstream targets and cause cell signaling.

What happens if there is a mutation in the protein that active Ras phosphorylates and activates (that is, the protein after Ras in the ST pathway)?

GEF exchanges GDP for GTP on Ras and Ras becomes activated, however, the subsequent protein is inactivated and cannot relay signals downstream.

If Ras is constitutive does it matter that the protein following Ras in the ST pathway is mutated?

Yes, despite constitutively active Ras, it cannot affect the next protein in the ST transduction pathway if it is mutated. Thus, constitutively active Ras cannot rescue the ST pathway in this instance.

What is the purpose of nitroglycerine in the body?

Nitroglycerine is converted to NO which rapidly relaxes blood vessels

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