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signal transduction Flashcards

Dr Danny Zisterer

1
Q

Communication by extracellular signals(so racist that David thought racist thoughts)

A

Synthesis
* Release of signalling molecule by signalling cell
* Transport of signal to target cell
* Detection of signal by specific receptor protein
* Transduction of signal (e.g. using second messengers)
* Response: change in cellular metabolism, function or
development triggered by receptor:signal complex
* Termination of signal

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2
Q

name the four types of cell surface receptors

A

G-protein coupled receptors (GPCR),
Ion-channel receptors,
Tyrosine kinase-linked receptors,
Receptors with intrinsic enzymatic activity.

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3
Q

example of g protein receptors

A

epinephrine

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4
Q

example of Ion-channel receptors

A

acetylcholine

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5
Q

example of Tyrosine kinase-linked receptors

A

erythropoietin

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6
Q

Receptors with intrinsic enzymatic activity

A

insulin

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7
Q

Lipophilic hormones with intracellular receptors

A

steroid hormones, thyroxine, Vitamin D

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8
Q

Lipophilic hormones with cell-surface receptors

A

prostaglandins

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9
Q

Hydrophilic hormones with cell surface receptors

A

Peptide hormones e.g. insulin and glucagon
Small charged molecules e.g. epinephrine and histamine

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10
Q

An example of a Signal Transduction Pathways

A

epinephrine+beta adergentic receptor = energy store mobalistaion

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11
Q

Common second messengers

A

cAMP, IP3, Calcium ion

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12
Q

what is the problem associated with secondary messengers?

A

Use of common second messengers in multiple
signalling pathways creates both opportunities (cross
talk) and potential problems

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13
Q

Protein phosphorylation is a common means of
information transfer but how? ie name the enzyme.

A

Specific enzymes, known as protein kinases
phosphorylate target proteins. ATP is the most common donor

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14
Q

what do protein kinases do?

A

transfer phosphoryl groups from ATP to specific serine, threonine
and tyrosine residues on specific proteins

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15
Q

what removes the phosphate groups hydrolytically?

A

Protein phosphatases

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16
Q

*Phosphorylation and dephosphorylation reactions are not
the reverse of one another.Why is this so?

A

Each is essentially irreversible
under physiological conditions.

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17
Q

Indeed a phosphate group does what?

A

A phosphate group adds two negative charges to the
protein-allows new electrostatic interactions to be formed. A phosphate group can allow for three hydrogen binds to be formed.

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18
Q

what is amplification?

A

when enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade.

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19
Q

Cyclic AMP activates protein kinase A (PKA)
by what?

A

altering the quaternary structure

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20
Q

g-protein receptors look like what?

A

contains seven helices that
span the membrane bilayer

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21
Q

how are G-Protiens activated by ligands?

A

Cytoplasmic loops and C-termini change
conformation in response to ligand
binding

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22
Q

name some of the Biological Functions Mediated by
GPCR or 7TM Receptor

A

Smell
Taste
Neurotransmission
Hormone Action
Hormone Secretion
Control of Blood Pressure
Embryogenesis
Development
Vision
Viral Infection

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23
Q

what was the first cellular g-protein receptor identified

A

Rhodopsin: takes part in visual signal
transduction

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24
Q

GCPR are the sites for what?

A

Target of almost half of all modern pharmaceutical
drugs (e.g. beta-blockers, anti-histamines and
various psychiatric drugs)

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25
in the heteromeric structure of G-proteins what transformation happens when binding
Once GTP binds to a subunit it changes conformation and dissociates from betay dimer
26
which is active and inactive G coupled protein forms?
GDP-bound (inactive) GTP-bound (active)
27
Effector enzymes
adenylate cyclase
28
b-Adrenergic receptor signalling pathway
begins with epinephrin binding to b-adrenergic receptor. GP is phosphorylase then the alpha subunit becomes dislodged and binds to adenylate cyclase. then to cyclic amp with is a secondary receptor.
29
HOW IS SIGNAL TRANSDUCTION BY THE GPCR TERMINATED?
Dissociation of signalling molecule from receptor & Phosphorylation of cytoplasmic C-terminus of receptor and subsequent binding of b-arrestin (desensitisation)
30
why is epinephrine needed in times of stress?
epinephrine produces food as a result of epinephrine/adrenaline binding to hepatic and adipose cells respectively (b-adrenergic receptor) Also,Epinephrine also binds to b-adrenergic receptors on heart increasing contraction rate which increases blood supply to tissues
31
when will receptor dissociate?
when levels of ephinephrine go below kd.
32
why are so many signals amplified by camp?
because some tissues inhibit amp for a response whilst others stimulate it .
33
A kinase anchoring proteins
AKAPs are multivalent adaptor proteins: one part binds to R subunits of PKA and another to the specific structure within the cell (e.g. microtubules)-confines the PKA to the vicinity of that structure.
34
PHOSPHOINOSITIDE CASCADE
ligand > receptor> activated g protien> activated phospholipase C>cleavage of phospholipid pip2 and ip3 and DAG.
35
pip 2 is cleaved into
DAG and IP3
36
The enzyme phospholipase C does what?
The enzyme phospholipase C cleaves PIP2 yielding IP3 and DAG
37
How are the IP3 - and DAG-initiated signals turned off
IP3 is rapidly metabolised to inositol which cannot open Ca2+ channel DAG may be (1) phosphorylated to phosphatidate or (2) hydrolysed to glycerol and fatty acids
38
Calcium ion is a widely used second messenger how?
Calcium binds tightly to proteins and induces conformational changes
39
what does calmodulin act as?
Calmodulin acts as a calcium sensor in nearly all eukaryotic cells.
40
When cytosolic Ca2+ level is raised above what? , calmodulin is activated
500nM
41
calmodulin has how many binding sites?
4 binding sites also think of your hand
42
After binding what surfaces get exposed
hydrophobic
43
calmodiun targets what
particular a-helix (in purple) in CaM kinase I
44
what signalling pathways get kicked off by tyrosine kinase receptors (2)
Insulin signalling pathway *EGF signalling pathway
45
Insulin receptor
is a dimer of two identical units (one a subunit and one b subunit linked by a disulfide bond Each b-subunit contains a protein kinase domain
46
how do you activate this receptor?
On binding of insulin, the cytoplasmic domain of the receptor which is a tyrosine kinase, becomes autophosphorylated on tyrosine OH groups resulting in activation of the insulin receptor.
47
the activation of insulin receptor
Binding of insulin to its receptor results in a conformational change which allows each b-subunit phosphorylate three key tyrosine residues on the other bsubunit. Phosphorylation of these three tyrosine residues in the activation loop (in red) of the kinase domain of the insulin receptor cause the loop to swing across the structure
48
what does akt 1 do?
Akt-1 moves through the cell phosphorylating target proteins (e.g. enzymes that stimulate glycogen synthesis and components important in trafficking the glucose transporter GLUT4 to the cell surface)
49
insulin increases the rate of glucose by how much?
15x
50
glucose transporters are stored where?
in vesicles
51
How are insulin receptor substrates (IRS) recruited to the activated insulin receptor?
The IRS attaches by its conserved SH2 domain to the phosphorylated receptor and it then becomes phosphorylated on tyrosine residues
52
there are 3 stages where amplification can occur when?
at enzymic reaction points
53
how is insulin signalling terminated?
1.Protein tyrosine phosphatases remove phosphoryl groups from insulin receptor 2.Lipid phosphatases remove the phosphoryl groups from inositol lipids (PIP3 to PIP2) 3.Protein serine phosphatases remove phosphoryl group from activated protein kinases e.g. Akt
54
what is unique about the EGF receptor
The EGF receptor is a dimer of identical subunits but, unlike the insulin receptor, the units exists as monomers until EGF binds. EGF so the dimer binds two molecules of ligand
55
what is the structure of EGF receptor?
EFG binding domain, transmembrane helix, kinase domain, c terminus tail.
56
what does the binding of EGF do?
EGF binding induces a conformational change allowing the dimerisation arm to extend from each receptor molecule.
57
what is the small G protien that is activated in the EGF pathway
RAS
58
EGF signalling leads to activation of a small G protein Ras outline this pathway.
1.Binding of EGF causes dimerisation and phosphorylation of tyrosine residues on C-terminal tail of receptor An adapter protein, GRB2, binds to phosphotyrosines on activated RTK GRB2 binds to Sos protein (a guanine nucleotideexchange factor or GEF) Sos promotes exchange of GDP-Ras (inactive) to GTP-Ras (active) Ras activates downstream signalling pathways
59
on the GRB 2 protein SH2 binds to
The SH2 domain binds to phosphotyrosine residues
60
SH3 domain
proline-rich regions on other proteins
61
How is the EGF signalling pathway terminated?
Phosphatases remove phosphoryl groups from tyrosine residues on EGF receptor and from serine, threonine and tyrosine residues in the protein kinases that participate in signalling cascade Ras possesses intrinsic GTPase activity. This is accelerated by GAPs (GTPase-activating proteins) which facilitate GTP hydrolysis
62
main changes for drosophila
EFG> BOSS EGF Receptor>sev GRB2 > Drk
63
Most common cancer gene in the human population
Ras Gene Most common mutation leads to loss of ability of Ras protein to hydrolyse GTP
64
constitutively active tyrosine kinase
Results in fusion protein known as BCR-ABL also- Translocation of genetic material between chromosomes 9 and 22 causes the c-abl gene (9) to be inserted into bcr gene (22)
65
leukaemia or (CML) have what?
CML cells express a unique target for anticancer agents .Gleevec is a tyrosine kinase inhibitor (TKI)- it inhibits BCR-ABL
66
what happens in the Her-2 gene?
The Her-2 receptor can signal even in the absence of ligand-it adopts an extended dimerization arm and is thus constitutively active.
67
Herceptin
enhanced receptor degradation or indeed, antibody-dependent cellular cytotoxicity
68
Cetuximab
This antibody inhibits the EGFR by competing with EGF for binding to receptor. The antibody also sterically blocks the dimerisation arm preventing it from extending
69
Notch signalling pathway-
juxtaposed ligands and receptors.
70
what does the notch signalling do?
It regulates cellular identity, proliferation, differentiation and apoptosis apoptosis is programmed cell death.
71
what is lateral inhibition
lateral inhibiton is adjacent and developmentally equivalent cells assume completely different fates
72
Basic operation of the Notch pathway
Key players: ▪ Delta-type ligand ▪ Receptor Notch ▪ Proteases ▪ CSL transcription factor
73
where is the notch signal receptor formed?
The Golgi then it is transported to cell surface.
74
what are the notch target genes
HES, CYCLIN D1 and C-MYC
75
How is Notch Signalling Pathway Switched Off?
An E3 ubiquitin ligase attaches multiple ubiquitin molecules to Notch-ICD thus targeting it to the proteasome * The proteasome is a large multifunctional protease complex in the cytosol that degrades intracellular proteins marked for destruction by ubiquitin
76
Two major classes of Notch inhibitors:
Y-secrase and monochrome antibody's
77
Protein synthesis can be globally regulated by
TOR Kinase
78
TOR kinase regulates what?
translation, transcription
79
what are the mamalian TOR kinase holders two different types
mTORC1 and mTORC2
80
what are the other two components for mtorc1
receptor and mLST8
81
Active mTORC1 controls protein synthesis by phosphorylating two key proteins
S6K1/2 and 4EBP1
82
S6K1/2
phosphorylates ribosomal proteins leading to an increase in the rate of protein synthesis
83
4E-BP1
inhibits interaction of a key translation initiation factor with mRNA so inhibits protein synthesis. When phosphorylated by mTORC1, 4E-BP1 releases the initiation factor thus stimulating translation initiation
84
an antagonistic relationship between the mTOR and AMPK pathways exists explain this
work opposingly
84
when is AMPK activated?
decrease in energy level, nutrient starvation or increase in the AMP/ATP ratio
85
what are the AMPK similar in plants
SnRK1.
86
SnRK1
SnRK1 is a central integrator of stress and energy modulating the expression of more than 1000 genes through phosphorylation of various transcription factors
87
how is plant snrk1 regulated ie. what sugars are responsible?
glucose6-phosphate (G6P) and trelahose-6-phosphate (T6P)

From cells to organisms (18 decks)

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