T5 Flashcards
Outline cellular signal reception and intracellular transduction.
- Receptor protein binds signal molecule
- Intracellular signaling proteins moves from receptor to
- Effector peoteins
What mediates communication between cells?
Extracellular sigbal molecules.
What are the three main classes of effector proteins?
- metabolic enzyme
- gene regulatory protein
- cytoskeletal protein
What is quorum sensing in bacteria?
Responding to chemical signals excreted into the intervellulsr space by other bacteria.
What different types of signal molecules are there?
“proteins, small peptides, amino acids, nucleotides, steroids, retinoids, fatty acid detivatives, and even dissolved gases”
What mechanisms does a cell have for signal presentation?
Diffusion, exocytosis and extramembraneous attachement.
Distinguish between the two receptor locayion.
Cell surface receptor and intracellular receptor.
A receptor-binding signal molecule is referred to as a…
…ligand.
Outline the four forms of intercellular signaling.
- Contact-dependent
- Paracrine
- Synaptic
- Endocrine
Outline contact-dependent signaling.
Bound ligand contacts bound receptor.
What type of intercellular communating has a local mediator?
Paracrine.
Explain paracrine signaling.
Cell signaling to cells in the immediate environment.
How does paracrine signaling differ from autocrine?
In autocrine signaling signals are mediated from a certain cell type to other cells of the same type. In paracrine signaling the emitting and receiving cells are of different histological types.
How is the effect of intercellular sigbaling limited so it becomes paracrine?
Rapid receiving cell uptake, destruction by extracellular enzymes, immobilization by extracellular matrix. Heparan sulphate proteoglycan signal-binding action. Antagonists binding to signal protein or its receptor.
What defines endocrine signaling?
Release of signal molecule into the blood for transportation.
What are the similarities between synaptic and endocrine communication?
Botch have (usually) very specific target cells.
How do synaptic and endocrine signaling differ?
Whilst synaptic signaling uses the same signal substance for many different cells, endocrine signaling uses very specific signaling molecules. Synaptic response is also (usually) quick and precise, whilst endocrine is long-term, strong and affects all cells that have the target receptor. Synaptic signals are diluted much less and thus more energy efficient.
What determines hiw quickly the results are seen?
What part of the receptor cell the signal affects. Quick: altered protein function (movement, secretion, metabolism). Slow: altered gene transcription.
Give an example of gap junction-mediated cell signaling.
Noradrenaline perfusion in liver when stimulated by nerves during low blood glucose.
What are the possible different functions that different signal combinations cause in different cells?
Survival, growth and proliferation, differentiation. Lack of signals leads to apoptosis.
How does acetylcholine affect heart muscle, skeletal muscle and salivary gland cells?
Decreases rate/force of contraction, induces contraction and induces secretion.
What is a morphogen?
A molecular signal emitted from a ‘signaling center’, the concentration of which determines what path of differentiation nearby cells take.
What factor plays in in determining hiw quickly a intracellular signal response is detected, if the response is measured in intracellular concentration of a certain molecule?
The half-time of the molecule.
Give an example of a nuclear receptor and how it activates gene transcription.
The ligand may bind to a transcription-activating complex, allowing it to activate transcription.
Describe the path of signal transduction from acetylcholine to NO?
AC activates NO-synthase in vascular endothelial cells. NO diffuses to vascular loose muscle, activating guanylyl cyclase. cGMP is produced and induces vascular relaxation.
Give examples of ligands transducted through gap junctions.
Ca2+ and cAMP. (not proteins)
Outline the different ways of signal desensitation/adaptation.
Receptor sequestrion, receptor down-regulation, receptor inactivation, inactivation of intracellular signaling protein, production of inhibitory protein.
Name the three main cell membrane receptors.
G-protein-coupled receptors, ion-channel-coupled receptors and enzyme-coupled receptor.
How does nitroglycerine mimic te effect of acetylcholine on the vascular system?
It turns into NO, relaxing the smooth muscle.
What types of NOS (NO synthase) are there?
eNOS (endothelial), nNOS (nerve and muscle) and iNOS (inducible NOS in mitochondria).
How is cellular NO produced?
By deMination of amino acid arginine by NOS.
How does NO and its breakdown tir in with erectyle disfunction meds?
Sildenafil blocks phosphodiesterase from breaking down cGMP that’s been produced in response to NO.
Can NO signal cells independently of cGMP?
Yes.
How does CO trasmit its signal?
Through stimulation of guanylyl cyclase.
Name some intracellular receptors that affect gene transcription.
Steroid and thyroid hormones, retinoids and vitamin D.
What is a nuclear receptor?
A protein coded in DNA that reacts with a signal molecule to affect gene transcription.
What is an orphan nuclear receptor and how is it recognized?
A nuclear receptor with unknown ligand. Recognized through DNA sequencing ( DNA-binding sequence found at same distance of C-terminal on all nuclear receptor proteins).
Steroid hormones include…
…gluco-/mineralocorticoids, steroid sex hormones and vitamin D (molting hormone edysone in insects).
How are the relatively insoluble nuclear receptor ligands transported extracellularly?
Bound to specific carrier proteins.
What nuclear receptors are bound adjacently to their gene independently of binding to their ligand?
Thyroid and retinoid receptors.
What nuclear receptor is found in the cytosol and enters the nucleus only after ligand binding?
Cortisol.
How are nuclear receptors inhibited from functioning withour a bound ligand?
Through action of a bound inhibitory protein.
Does binding of ligand to its receptor always induce gene transcription?
No, it can also repress.
How is the response to signals to nuclear receptors classified?
Primary (protein production) and seconday (protein production resulting from former proteins) response.
Why does a certain signsl molecule not elicit the dame response in all cells?
Because genes need typically an array of gene regulatory proteins in order to be transcribed in a certain manner.
What is signal transduction?
Conversion of an extracellular signal to an intracellular one.
What’s a signal transducer?
An extracellular receptor thta mediates the signal into the cell.
Give examples of small intracellular mediators/second messengers.
Ca^2+ and cAMP in the cytosol, diacylglycerol in the plane of the plasmamembrane.
Name the different possible steps in signal transduction.
- Relaying (with/without aid of scaffold)
- Amplification (when multiple amplification->signal cascade)
- Integration para-pathway inputs
- Spreading signal to other pathways
- Anchoring of signal proteins
- Modulation of activity of other signal proteins
Describe how a protein can function as a molecular switch?
Through toggleing between an active and inactive state, determined by binding of other molecules to the protein.
What two main classes of protein switches are there?
Phosphorylation-activated/inactivated proteins and GTP-binding proteins.
What two enzymes are required for a phosphorylation-activated/inactivated molecular switch protein to function?
A kinase and a protein phosphatase.
What’s a phosphorylation cascade?
The intracellular phenomenon of kinases phosphorylating and thus activating downstream kinases, which further activate downstream kinases etc.
How can a transuced signal be spread to other signaling pathways?
For example through phosphorylation cascades.
Name the two main types of kinases that work as intracellular signaling proteins.
Serine/threonine-kinase and tyrosine kinase.
Describe GTP- binding protein activation-deacyivation mechanisms.
When GTP binds it causes activation and GTPase activity. Release of GDP (due to low concentration) inactivates the GTP-binding protein.
Discern between trimeric GTP-binding proteins and monomeric GTP-binding proteins.
Trimeric GTP-binding proteins are found in connection with G-protein-coupled receptors, and monomeric GTP-binding proteins as single signal relaying units.
What regulatory proteins control the GTP-binding proteins and how do they function?
GAPs (GTPase-activating) proteins increase rate of bound GTP hydrolysis and GEFs (guanine nucleotide exchange factors) activate monomeric GTPases by promoting release of GDP in exchange for GTP.
What do coincidence detectors do?
They integrate multiple signals, soluble and ones from the ECM to spur the cell in survival.
What constitutes an intracellular signaling complex?
A scaffolding protein and signaling proteins.
What are the benefits of a signaling complex vs. loose signsl proteins?
Speedy sequential activation, efficiently and selectively in responsively to extracellular signal withour cross-talk.
What may result of transient signaling complexes formed around the intracellular part of receptors?
Phosphorylation of cytoplasmic tail of receptor (docks other signaling proteins) or production of modified phospholipids (phosphoinositides) in adjacent part of the cell membrane that then recruits other signaling proteins when being hyperphosphorylized.
What is induced proximity based on?
The possibility of some signaling proteins being activated dimply from being in proximity with others.
What are interaction domains?
Small, highly concervative parts of proteins that do not change shape during interaction. “Recognized motifs can be short peptide sequences, phosphorylated/ubiquitylated amino acids or another protein domain”.
Why might a signal response seem gradual despite almost switch-like signal response in the cell?
Due to gradual buildup of extracellular sigbals to be measured.
What factors make for almost switch-like signal responses in cells?
- Binding of more than one signal molecule to its downstream target protein
- When an intracellular signal protein requires phosphorylation at multiple sites
- Other cooperative responses such as same signal activation of one enzyme and deactivation of another with opposite effect (gluconeogenesis and adrenaline)
Describe the function of a bistable positive-feedback system.
A runaway function, self-sustaining so that it continues with or without the original activation signal. Needs separate deactivation signsl to be turned off, or runs out of substrate.
How do negative feedback systems differ when comparing long and short delay?
Steady oscillation with max. at max. of control vs. change detector-behaviour (spike+decrease and plateau)
What biomolecular mechanism lies behind signal adaptation/desensitization?
Negative feedback with short delay.
Methylation or phosphorylation of a receptor can…
inactivate it.
What are the six classes of enzyme-coupled receptors?
- Receptor tyrosine kinase
- Tyrosine-kinase-associated receptor
- Receptor serine-threonine kinases
- Histidine-kinase-associated receptors
- Receptor guanylyl cyclase
- Receptorlike tyrosine phosphatases
What’s the function of activated RTKs (receptor tyrosine kinases)?
To phosphorylate themselves and intracellular signaling proteins, causing them to bind.
What’s a deuterostome?
An organism that develops embryonically with the anus as the first opening.
What’s the largest class of cell-surface-bound extracellular signal proteins, what’s their receptor and what’s special about it?
Ephrins. The ephedrine receptor Eph receptors can act as both ligands and receptors (bidirectional signaling). Ephrins and their receptors direct cell growth.
What receptor family are ephrins part of?
RTKs
What does induced proximity and dimerization lead to in RTKs?
Transautophosphorylation.
Describe the dominant-negative way of silencing receptor response of RTKs.
Inactivating dimer components are produced from transfected DNA, leading to inactivation of signal progression mechanism.
Name some signal proteins acting via RTKs.
EGF, IGF and insulin receptor.
What’s the function of phosphorylation of the tyrosine side chain in TRKs?
To activate the receptor, attract and bind signal protein thus activating it (possibly phosphorylate it).
How does IGF1 differ from most TRKs?
It tetramerizes, vs. dimerization in most TRKs.
How do signaling proteins bind to phosphorylated TRKs?
With aid of SH2 domains.
WhT’s the role of Src?
To bind to phosphorylated TRKs (phosphotyrosine) and then phosphorylate signaling proteins.
What’s the role of the SH3 domain on signaling proteins?
To affect other signaling pathways
Are SH2-aided signaling proteins always potential carriers of the signal?
No, they may inhibit signal transgression through negative feedback.
How are RTKs seuqestered from the cell membrane?
Through monoubiquitylayion.
Does ligand-induced endocytosis of RTKs always inhibit signaling?
No. Axons for instance use this for transporting of signals across long distances.
How do RTKs activate Ras?
Through SH2/SH3 docking.
Give an example of a signal hub.
Ras and Rho of the Ras superfamily.
What does Ras do.
Contains lipid groups that help anchor protein to the cytoplasmic side of the cell membrane.
Non-functioning of Ras-inhibition leads to…
tumours.
Ras is active when…
GTP is bound.
What do Ras-GEFs and -GAPs do?
Stimulates new binding of GTP (activation) and GTP hydrolysis respectively (inactivation).
How is Ras activated by RTKs?
Through indirect coupling of RTK to Ras-GEF through adaptors.
How are RTK phosphorylation reversed?
By action of tyrosine-specific protein phosphatases.
Describe the action of the MAP (mitogen-activated protein kinase module) that’s activated by Ras.
- Active Ras activates MAPkkk (RAF) that activates/phosphorylates…
- MAPkk (Mek) that activates/phosphorylates…
- MAPk (Erk) that affects/phosphorylates protein activity and gene transcription
Which steps of the MAP kinase module require ATP.
All.
How does MAP kinase module elicit a switch action signal?
Through positive feedback.
How is negative feedback established in MAP kinase module?
Through increasing concentration of dual-specifity protein phosphatase which removes phosphate from both tyrosine and threonine (aniactivayion).
How does Erk affect Raf?
Inactivates (negative feedback).
What’s the main task of scaffold proteins in MAP kinase modules?
To separate parallell signal routes (mating and osmolarity responses in yeasts ex.)
What is the purpose of Rho family GTPases?
To functionally couple cell-surface receptors to growth-collapse of cytoskeleton through polarity, motility and adhesion. Also cell-cycle progression, gene transcription, membrane transport, cell migration/axon growth. They mediate cytoskeletal responses to activation of guidance receptors.
How do Ras and Rho family siffer in location when activated?
Ras is membrane boubd, Rho family is found in cytosol bound to GDIs (guanosine dissociation inhibitors). GDIs prevent GTPases from interacting with Rho-GEFs.
What’s the most common receptor type for Rho-family?
Ephrins.
How are PI 3-kinases (phosphoinositide kinase) positioned for activation of PIs (phosphatidylinositols)?
Bind to intracellular tail of RTKs.
What do PI 3-kinases do?
Activate phosphoinosityls through phosphorylation, allowing them to dock proteins.
What does the PI-3-kinase-Akt signsling pathway play a role in?
Animal cell survival and growth.
How does the IGF family act through the PI-3-kinase-Akt pathway?
Binding to RTK activates PI 3-kinase which produces PI(3,4,5)P_3. PIP_3 recruits two kinases to plasma membrain via Akt. Akt phosphorylates target proteins.
Name a target for Akt, and its function.
Bad, apoptosis inhibitor-binder.
Give to interdependent pathways that aid cell growth through activation of mTOR.
PI 3-kinase-Akt (inactivates Tsc2) and Ras-MAPk.
What is FAK and where is it found?
Focal adhesion kinase, found at focal adhesions where it aids Src in binding.
What signaling pathway do cytokine receptors activate?
JAK-STAT signaling pathway.
Describe the JAK-STAT signaling pathway.
- JAK-bound cytokine receptors dimerize
- Cross-phosphorylation of JAKs
- Activated JAKs phosphorylate receptors on tyrosines
- STATs dock bilaterally on cytokine receptors via SH2 domains
- STATs are phosphorylated by JAKs
- Dimerization of STATs and translocation to nucleus
- Binding to cytokine response element on gene and transcription initiation
How do signal proteins of TGFβ superfamily (transforming growth factor-β) translocate their signals?
Through receptor threonine/serine kinases ans Smads.
Describe Smad dependent signaling pathway used by TGFβ.
- TGFΒβ binds to RTK
- Type II receptor phosphorylates Type I receptor
- Type I receptor phosphorylates Smad2/3
- Dissociated Smad2/3 oligomerizes with Smad4
- Oligomer translocates to nucleus, binds gene regulatory proteins and initiates transcription
What are Smurfs?
Smad ubiquitylation regulatory factor.
Are serine/threonine and tyrosine protein kinases related in some manner?
Yes, structurally.
How is the two-component signaling pathway, used by bacteria for chemotexis, activated?
By histidine-kinase-associated receptors.
What’s the basis for bacteria homing or deflection?
Binding of attractant or repellant, inhibiting or activating phosphorylation. Dignal transduction is based on adaptation through reversible receptor methylation.
Even though they’re all latent gene regulatory proteins, how do Smad and STAT differ from NFκB?
In activation mechanism. Phosphorylation vs. highly selective protein degradation.
Which cells display Notch receptors and which express the Delta ligand?
Notch receptors are found on potential neural progenitor cells. Delta ligand is expressed on differentiating neural cells, interacting with the Notch receptor to inhibit differentiation in receptor cells.
What is lateral inhibition?
One cells inhibiting of neighbouring cells from differentiating, ex. by Notch-Delta interaction.
What happens with the Notch receptor when binding to Delta ligand?
Successive proteolytic cleavage and translocation of intracellular tail to nucleus. Binding to protein complex (ex. Rbpsuh) and transcription of Notch target gene.
What are Wnt proteins and what is their function?
Secreted signal molecules that act as local mediator/morphogen on frizzled receptors to inhibit β-catenin degradation in intracellular signaling path.
Where is most β-catenin found in epithelial cells?
In association with cadherin of adherens junctions.
How does the stable β-catenin act in cells after Wnt-signaling?
They bind to gene promoter sequence, associating with coactivators.
What different forms of hedgehog protrins are tere and what strctursl features define them?
Sonic, Desert and Indian hedgehog. Coupled with cholesterol and a fatty acid.
What transmembrane proteins mediate responses to Hedgehog proteins?
Patched, Smoothened and iHog. Downstream by CI (cubitus interruptus, not transmembraneous).
Describe the signal path of Hedgehog-mediated signaling.
- Binding to Patched.
- Smoothened is recruited by vesicle transport to cell membrane.
- CI proteolysis is inhibited.
- Intact CI translocates to nucleus and activates Hedgehog target gene transcription.
What is the effect of the lack of the Hedgehog signal?
Inhibition of Hedgehog gene transcription through proteolysis of CI.
Describe the activation of the NFκB pathway by TNFα.
- TNFα trimer binds to receptor
- IKK (IκB kinase kinase) complex phosphorylates IκB
- IκB is polyubiquitylated and degraded
- NFκB is thus liberated and translocated to nucleus and target gene.
- Transcription.
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