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Molecular Medicine > Unit 1 - Signal Transduction > Flashcards

Unit 1 - Signal Transduction Flashcards

1
Q

Molecular

A

activation of enzyme, generation/synthesis of metabolite and its degradation

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2
Q

cellular

A

number of mitochondria regulated in a cell may divide, split, fuse

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3
Q

tissue/organ

A

no of cells or cell types are tightly regulated

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4
Q

4 levels of regulation in living organism

A

molecular

cellular

tissue/organ

organism (neuro-endocrine)

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5
Q

main mechanims of integration of the levels of regulation

A

HPA axis

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6
Q

what is the target of regulation

A
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7
Q

definition of signal transduction

A

process linking the signal-activated receptor and the biological response

there is a common logic in the structure of signal transducers and in the mode of their function

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8
Q

how is regulation initiated and and how does it flow

A

initiated by the signal (information) reaching the cell or formed within the cell

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9
Q

EC signal molecule → receptor protein → IC signalling proteins → target proteins

A
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10
Q

what can a signal be, based on their origin

A

from environment - pin, temp, light, smell

from organism - hormones, cytokines, metabolites

from within the same cell - DNA damage, ROS

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11
Q

what can a signal be if chemical

A
  • proteins - GH
  • peptides - insulin, neuropeptides
  • AAs, derivatives - thyroxine, dopamine, epinephrine
  • lipids - PGs, platelet activating factor
  • ions - Ca2+, Cl-
  • nucleotides - adenosines with specialised receptors on their surface
  • gases - nitric oxide (produced by endothelial cells – trigger smooth muscle relaxation and vasodilation)
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12
Q

types of signal transmission

A
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13
Q

what is the significance of ligand binding

A

specificity

amplification

co-ordination of response - the same receptor may be present on a number of cells

cell specific response - by regulating the number and function of receptors

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14
Q

example of disease that involves a cell-specific response

A

type 2 diabetes

autoinhibitory receptors are present on cells become inactivated and unresponsive

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15
Q

types of receptors

A

cell surface/transmembrane receptors

nuclear receptors

cytosolic receptors

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16
Q

receptors for what hormone are present on a wide variety of cells

A

cortisol

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17
Q

amplification system

A

Uniform response of cell

e.g. If a cell triggers lipid degradation, whole lipid synthesis across the cell has to shut down and lipid degradation must occur

Net 0 effect - what 1 process achieves, the other will undo

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18
Q

allosteric regulation

A
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19
Q

interconversion cycle

A

NOTE: enzyme specific - some are active phosphorylated, some are active dephosphorylated

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20
Q

Akt/Protein Kinase P interconversion cycle - 1st mechanism

A

inactive Akt → Akt by 2 mechanisms:

FIRST

phosphorylated serine 473 interacts with the linker between the kinase and pH domains

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21
Q

2nd mechanism in Akt/protein kinase P interconversion cycle

A

phosphorylated serine 477 and threonine 479 result in the displacement of the pH domains

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22
Q

enzyme cascade

A
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23
Q

acceptors

A

all signal transduction pathways culminate to control of function of proteins (mostly enzymes, ion channels, transporters), which are involved directly in formation of biological response

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24
Q

2 categories of acceptors

A

control of protein amount

gene expression

protein degradation

protein stabilisation (tumour suppression gene P53)

control of existing proteins

without covalent modification of the protein (P) - Allosteric activator binds to an allosteric enzyme complex

with covalent modification of the protein - reversible and irreversible (cleavage of 3 forms of enzymes e.g. digestive enzymes involved in cleavage of trypsinogen to inter trypsin)

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25
Q

tumour suppression gene P53

A

regulated by protein stabilisation

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26
Q

mechanisms of hormonal regulation

A
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27
Q

4 types of membrane bound receptors

A

ion channel enclosing receptors

7 transmembrane domain receptors

1 hydrophobic domain receptors (R with enzyme activity, R with no enzyme activity)

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28
Q

ligands that activate membrane bound receptors

A

hydrophilic

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29
Q

signalling via ion channel-enclosing receptor example

A

nicotinic ACh receptor

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30
Q

structure of nicotinic ACh receptor

binding results in

A

pentamer (2 x α, β, γ, δ)

subunits surround a central pore

2 Ach binding sites from the pore

their binding is co-operative and leads to channel opening

channel is selective for divalent cations (+ve) - Na+ and Ca2+

hyperpolarisation with AP triggered

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31
Q

ION CHANNEL-ENCLOSING RECEPTORS

GABA, glycine, ACh, glutamate, serotonin

  1. receptors
  2. amplification systems
  3. acceptors
  4. biological response
A
  1. on the plasma membrane
  2. channel-transmitted ions
  3. membrane ion channels (e.g. VG Na+ channels)
  4. membrane depolarisation, hyperpolarisation, muscle contraction etc
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32
Q

glycine ion selectivity

A

Cl-

HCO3-

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33
Q

GABA ion selectivity

A

Cl-

HCO3-

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34
Q

ACh ion selectivity

A

Na+

K+

Ca2+

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35
Q

glutamate ion selectivity

A

Na+

K+

Ca2+

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36
Q

serotonin ion selectivity

A

Na+

K+

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37
Q

ION CHANNEL-ENCLOSING RECEPTORS

IP3, cGMP, cAMP, ATP

  1. receptors
  2. amplification system
  3. acceptors
  4. biological response
A
  1. on IC membranes
  2. channel-transmitted ions
  3. myosin, membrane ion channels
  4. muscle contraction, depolarisation, hyperpolarisation, activating of energy producing metabolic pathways also
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38
Q

IP3 ion selectivity

A

Ca2+

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39
Q

cGMP ion selectivity

A

Na+

K+

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40
Q

cAMP ion selectivity

A

Na+

K+

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41
Q

ATP ion selectivity

A

K+

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42
Q

overview of signalling system of ion channel-enclosing receptors

A
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43
Q

example of signalling via 7-transmembrane domain receptors

A

β adrenergic receptors

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44
Q

structure of 7 transmembrane domain receptors

A

amino terminal lies on EC side

carboxyl-terminal is in the cytosol

ligand sits in a pocket formed by transmembrane helices

upon R activation, the R binds a G protein (GPCRs)

3rd TM domain recognises the G protein

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45
Q

amplification system of G-protein activated adenylate cyclase

A
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46
Q

how does protein kinase A regulate the acceptor

A

PKA when activated by cAMP can penetrate the nuclear membrane

It can then phosphorylate CREB

When phosphorylated, it is ACTIVE and helps to initiate gene expression

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47
Q

acceptors of protein kinase A

A
  • enzymes
  • structural proteins - troponin, myosin light chain kinase
  • ion channels - IP3-sensitive Ca2+ channel
  • transcription factors (cAMP response element binding protein - CREB)
48
Q

biological responses induced by adenylate cyclase system

in what structures is it present

A

Liver

adipocytes

muscle

adrenal cortex

T cell

Olfactory cells

crypt cells

SM cells

49
Q

biological responses induced by adenylate cyclase system

LIVER

A

glycogenolysis

glyconeogenesis

glucolysis

gluconeogenesis

lipid synthesis

β oxidation

cholesterol synthesis

50
Q

biological responses induced by the adenylate cyclase system

ADIPOCYTES

A

lipid breakdown

51
Q

biological responses induced by the adenylate cyclase system

adrenal cortex

A

synthesis of many steroid hormones

ACTH regulated aldosterone secretion

52
Q

biological responses induced by the adenylate cyclase system

OLFACTORY CELLS

A

sensitivity to odorants

53
Q

biological responses induced by adenylate cyclase system

CRYPT CELLS

A

Cl- secretion

54
Q

biological respones induced by adenylate cyclase system

SM CELLS

A

inhibition of contraction

55
Q

biological responses induced by adenylate cyclase system

MUSCLE

A

glycogenolysis

56
Q

biological responses induced by adenylate cyclase system

T CELL

A

proliferation

death

57
Q

Amplification system - G protein activated phospholipase C

A

IP3 = ion channel

58
Q

catalytic rxn of PLC

A

PLC can be activated via G proteins or by Tyr phosphorylation

membrane bound phosphatidyl 4, 5 bisphosphate is hydrolysed to membrane bound diacyl-glycerol and cytosolic ionositol 1, 4, 5-trisphosphate

59
Q

activation of PLC?

A

via G proteins or by Tyr phosphorylation

60
Q

amplification of G protein activated PLC

A
61
Q

targets of calcium

A

calcium activates protein by directly binding or binding to a calcium-activated regulatory subunit

62
Q

acceptors that are directly activated by Ca2+

A

tissue transglutaminase

protein kinase C

phospholipase A2

calpain

DNases

63
Q

calcium-sensing regulatory subunits

functions

A

calmodulin regulated proteins

glycogen phosphorylase kinase, muscle contraction, calmodulin regulated protein kinase

64
Q

AAs associated with PKC

A

Ser

Thr

65
Q

targets of PKC

A

cell surface receptors - EGF, insulin, CD3

enzymes - raf1 kinase, GAP-p21 ras

ion channels - Na/H+ exchange

proteins in cell cycle control - DNA topoisomerase

nuclear factors - NFκB

proteins in cytoskeleton - MARCKS

66
Q

PLC-induced biological responses

A

liver glycogenolysis (adrenaline α1, vasopressin)

thrombocyte aggregation (PAF, thromboxan)

thrombocyte serotonin secretion

mastocyte histamine secretion (IgE)

pancreas digestive system enzyme secretion (cholecystokinin)

insulin secretion

adrenal chromaffin cell adrenaline secretion

adrenal cortex aldosterone secretion (Ang II)

SM contraction (PGE2)

cell proliferation

differentiation

programmed cell death

67
Q

signalling system via 7-transmembrane domain receptors

A
68
Q

signalling through 1-hydrophobic domain receptors carrying enzymatic activity

  • give an example
A

receptor tyrosine kinases (in their C terminus) - insulin receptor

69
Q

receptor tyrosine kinase

how many present

how do the domains differ

what are the receptors for

A

58 in humans, in 20 sub-families

1 transmembrane region

variable EC ligand binding domain

IC tyrosine kinase domain

receptors for growth and survival factors - drive cell proliferation, cell survival, cell differentiation

70
Q

GOF mutation in TK receptor

A

GOF ⇒ constitutively active in the absence of their ligand

they will drive constant cell proliferation, cell survival making these cells resistant to drugs

71
Q

ligands of TK receptors induce

A

RTK dimerisation, leading to activation

72
Q

what do the phosphorylated tyrosines act as

A

docking sites for signal transducing proteins

73
Q

phosphotyrosine residues act as binding sites for

A

enzymes and adaptor proteins

74
Q

what are adaptor (scaffold) proteins

A

proteins with platforms to bind multiple proteins

ability to bring protein complexes together

proteins with SH2 (Src homology domain 2) and PTB (phosphotyrosine binding) domains can dock on phosphorylated tyrosines of RTK

the type of adaptor protein determines the downstream signalling and the biological response

75
Q

3 main signal transduction pathways induced by RTKs

A
76
Q

what is Ras

what amplification cascade does it activate

A

a small GTPase, similar to G proteins

activates the MAPK amplification cascade

77
Q

Ras activating enyme

A

Raf (Ser/thr kinase)

78
Q

RAS signalling drives

A

cell division

79
Q

Ras and cancer

A

Ras (HRAS, NRAS, KRAS)

one of the most frequently mutated oncogenes in human cancers

80
Q

what is Ras unable to do

A

single subunit protein so not able to replace GDP with GTP

hence GEF protein helps with this - removes GDP and replaces it with GTP

81
Q

Ras pathway

A

Grb2 (scaffold) binds to P-Y via its SH2 domain

Grb2 has 2 SH3 domains, which bind Sos

Sos = guanine nucleotide exchange factor that activates Ras

Ras activates Raf

Raf is a serine threonine kinase and activates mitogen activating protein kinases

82
Q

how and what does Ras induce

A
83
Q

3 main Ras proteins in the body

A

KRAS

NRAS

HRAS

84
Q

Ras mutations and cancer

A

GOF - affects GTP binding

85
Q

phosphatidyl ionositol 3 kinase pathway

  • how is it activated
A

by RTKs

(PLC is seen both with 7 TM receptors but also RTKs)

86
Q

what does PI3K phosphorylate

A

the membrane lipid phosphatidyl ionositol 2-phosphate

87
Q

structure of PI3K

A

regulatory and catalytic subunit

both subunits have multiple protein binding motifs and recognition motifs (SH2, SH3)

1 of the most frequently mutated pathways in human cancers

88
Q

phosphatidyl ionositol 3 kinase pathway

A
89
Q

FoxO

A

blocks cell signalling

Forkhead transcription factor

regulates expression of Bim

90
Q

GLUT4

A

glucose uptake into cells

activated by Akt

91
Q

GSK3

A

glycogen synthase kinase

Akt inhibits GSK3

metabolic adaptation

leads to glycogen metabolism, cell cycle progression

92
Q

mTOR

A

metabolic adaptation

protein synthesis for cell proliferation

(activated by Akt)

93
Q

Bad, Bim

A

cell survival

Akt inhibits Bad, Bim, Bax (which are all pro-apoptotic)

94
Q

what does activated Akt do

A

regulates receptors via phosphorylated serine and/or threonine residues on them

95
Q

what are inhibitors of PI3K used to treat

A

chronic lymphocytic leukaemia

96
Q

PI3K and Akt are

A

proto-oncogenes

(GOF ⇒ constitutively active - Drive proliferation, drug resistance)

97
Q

signalling system of receptor tyrosine kinases

A
98
Q

3 groups of signal transduction pathways

A

membrane bound receptors

cytosolic receptors

nuclear receptors

99
Q

types of membrane bound receptors

A

ion channel-enclosing receptors

7-TM receptors (β adrenergic)

1 hydrophobic domain receptors (with or without enzyme activity)

100
Q

requirement for IC receptors

A

ligands must be membrane permeable

101
Q

examples of IC receptor ligands

A

steroid hormones

lipophilic vitamins

small molecules e.g. NO and H2O2

102
Q

example of cytosolic receptor

what is its ligand

A

soluble guanylate cyclase receptor

receptor for NO

103
Q

functions of NO

A

regulation of SM relaxation

platelet aggregation

neurotransmission

104
Q

where does the synthesis of NO occur

A

in endothelial cells, neuronal cells and macrophages

105
Q

enzymes that produce NO

what are their isoforms

A

nitric oxide synthases (NOS)

neuronal NOS

endothelial NOS

inducible NOS

** expression is not restricted to these tissues

106
Q

how is the synthesis of NO controlled

A

by hormones, cytokines, bacterial endotoxins

VIA

  1. regulating the IC Ca2+ level (eNOS, nNOS)
  2. regulating the synthesis of NOS on gene level (iNOS)
107
Q

soluble guanylate cylcase-induced signalling

A
108
Q

what are nuclear receptors

A

transcription factors - intitiate gene transcription

109
Q

nuclear receptors intitiating gene transcription

A
110
Q

what are class I nuclear receptors

A

inactive receptor located in cytosol

111
Q

what complex keeps the receptor inactive

A

HSP complex

112
Q

what happens when the hormone binds to the nuclear receptor

A

dissociation of heat shock proteins

dimerisation

translocation to the nucleus

113
Q

what family does the class I NR belong to

A

steroid receptor family

  • progesterone - PR
  • oestrogen - ER
  • glucocorticoid - GR
  • androgen - AR
  • mineralocorticoid - MR
114
Q

nature of changes in gene transcription mediated by steroid receptors

A

relatively slow in onset yet result in long-term changes in gene expression

115
Q

where are class II nuclear receptors found

A

retained in the nucleus even when no ligand is bound

116
Q

ligand binding to class II nuclear receptors causes

A

dissociation of corepressor protein

recruitment of coactivator protein

recruitment of additional proteins including RNA polymerase to the NR/DNA complex to transcribe DNA into mRNA resulting in biological response

117
Q

examples of class II nuclear receptors

A

retinoic acid receptor

retinoid X receptor

thyroid hormone receptor

vit D receptor (VDR)

peroxisome proliferator-activated receptor (PPAR)

Molecular Medicine (7 decks)

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