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BMS2021 > TOPIC B CELL TALK: Communication networks inside and outside cell > Flashcards

TOPIC B CELL TALK: Communication networks inside and outside cell Flashcards

1
Q

What is paracrine signalling?

A
  • Local signalling
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2
Q

What is endocrine signalling?

A
  • Long distance–> hormone related

- Released from tissue that is FAR from target cell

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3
Q

What are the three different types of effector proteinsproduced from signalling pathways and what are their actions?

A
  1. Metabolic enzyme (altered metabolism)
  2. Cytoskeletal protein (altered shape or movement)
  3. Transcriptional regulator( altered gene expression)
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4
Q

What are the two features of signalling?

A
  1. SPECIFICTY `

2. AMPLIFICATION

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5
Q

What is specificity?

A
  • Signal molecule that fits binding site on complementary receptor (others don’t fit)
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6
Q

What is amplification?

A
  • Enzymes activate OTHER enzymes

- no. of affected molecules INCREASES geometrically in enzyme cascade

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7
Q

What occurs in negative feedback?

A
  • Build up of product turns off original activator
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8
Q

What is positive feedback?

A
  • build up of product amplifies pathway
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9
Q

What type of signal transduction is FAST acting?

A
  • Altered protein function (proteins already synthesised and ready to go)
    e. g. insulin INCREASING GLUT receptors in membrane
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10
Q

Which type of signal transduction is SLOW acting?

A
  • Altered protein synthesis (and expression)

e. g. If cell wants to synthesise more receptors

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11
Q

What are the three different classes of hormone?

A
  1. Polypeptide/protein hormones e.g. Insulin
  2. Amine –> Adrenaline
  3. Steroid–> Estrogens/testosterone (passes through cell membrane freely)
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12
Q

What 4 things is cell communication required for?

A
  1. Regulation of development
  2. Organization into tissues
  3. Control of growth, death, and division
  4. Coordination of diverse cellular activities
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13
Q

What is the biggest class of hormones?

A
  • Polypeptide/protein
    e.g. insulin/glucagon
    leptin, GH, TRH LH Growth factors
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14
Q

Why are polypeptide/portein hormones stored in secretory vesicles for up to 1 day vand what form are they in?

A
  • Because otherwise it could be degraded

- Stored as a PROHORMONE (inactive form)

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15
Q

What is the lifetime of protein hormones circulating in the blood freely?

A
  • Minutes before they are degraded
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16
Q

What is the secretion of polypeptide/protein hormones regulated by?

A
  • Other hormones
  • metabolites
  • CNS
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17
Q

What is the formation of mature insulin from immature insulin?

A
  • Preproinsulin—(signal sequence chopped off)—-> Proinsulin—(c peptide chopped off)—-> Mature insulin
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18
Q

What chains does insulin have and what are they joined together by?

A
  • Alpha and beta chain

- Joined together by disulfide bonds

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19
Q

What is insulin synthesised by?

A
  • The beta cells of pancreas as PROHORMONE
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20
Q

What are peptide.amine hormones derived from and what are they ?

A
  • Tyrosine
  • Adrenaline and NA
  • T3 and T4
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21
Q

Where are NA and A secreted from?

A
  • Adrenal medulla
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22
Q

If NA and A are secreted freely in the blood, how long will they last for?

A
  • Seconds (so short lifetime)
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23
Q

What are the 3 different types of cell surface receptors?

A
  1. Ion-channel coupled receptors
  2. G-protein coupled receptors (activated by GTP binding)
  3. Enzyme coupled receptors (variable) –> Receptors itself is enzyme
    - can have catalytic domains OR associated with enzyme close to membrane
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24
Q

Where does the signalling molecule bind to in nuclear receptors?

A
  • Ligand binding domain (distinct from other domains)
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25
Q

In nuclear receptor pathways, what MAY NEED TO occur before gene transcription can happen?

A

-may need to have coavticator proteins binding (can become part of transcription activating domain)

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26
Q

What happens in nuclear receptor pathways when the ligand binds?

A
  • there is conformational change q
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27
Q

What other important domain is part of the intracellular receptor?

A
  • DNA-binding domain
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28
Q

What are the two pathways that can be active once G protein coupled receptor is activated?

A

`1. Cyclic AMP pathway (second messengers)

2. Inositol phospholipid pathway

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29
Q

What features are common to all G protein coupled receptors? -

A
  • Cell surface receptors
  • 7 transmembrane segments
  • signalling molecule can activate MULTIPLE GcPRS
  • ALL use G proteins to relay a signal
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30
Q

What is the structure of a G protein? (and subunits)

A
  • Trimeric G protein complex

- Has alpha, beta and gamma subunits - in some types may only have 1 or 3 subunits

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31
Q

What can the alpha subunit bind on a G protein?

A
  • GDP (inactive form)

- GRP active form

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32
Q

What do the phospholipid tails on the alpha and beta subunits of the G prtoein do?

A
  • Anchor subunits into membrane
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33
Q

What are the 7 steps of the activation of a G protein? (Last step: when is switch turned off?)

A
  1. Ligand binds to G protein coupled receptor
  2. RECEPTOR changes conformation, interacts with inactive GDP bound G protein
  3. Causes G protein to EJECT GDP and replace with GTP
  4. This exchange causes conformational change
  5. G protein: binding GTP releases receptor
  6. It interacts with one or more effectors —> active protein–> delivers message
  7. Switch is turned off WHEN G PROTEIN HYDROLYSES its own bound GTP–> GDP (after time)
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34
Q

What happens in G protein coupled receptors when GTP is bound to the alpha unit?

A
  • It DISSOCIATES from Beta or gamma units so they can activate another complex/pathway)
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35
Q

What is the role of a second messenger?

A
  • Internal messenger that activates secondary pathways in cell e.g. cAMP–> activates PKA and self transcription
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36
Q

What occurs in the universal (not individual cell type) Inostiol Phospholipid pathway?

A

Signal molecules comes in from EXTRACELLULAR source and activates receptor–> induces conformational change–> activates G protein complex (beta and gamma subunits)—> Activates protein (phospholipase C–this cleaves phospholipid)—> Activated phospholipase C acts on INOSITOL PHOSPHOLIPID (IP2) in membrane and cleaves it from DAG (diacylglycerol) in membranre—> this FORMS IP3 (secondary messenger)
- IP3 binds to ligand gated ion channel–> Casues Ca2+ efflux from ER —> Ca2+ activates PROTEIN KINASE C (PKC) —> then activates other processes (cellular) like gene trancription and muscular contraction

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37
Q

What does PKC (protein kinase C) need to be activated in the insosital phospholipid pahtway?

A

Needs BOTH DAG (diacylglycerol) and and Ca2+ to be activated

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38
Q

What occurs in the cyclic AMP pathway of G protein coupled receptors?

A

Membrane bound recpetor: Adenylyl Cyclase converts ATP–> cyclic AMP

  • Only alpha subunit involved
  • cAMP then activated in signalling molecule in cell (second messenger)
  • Inactive PKA (4 subunits–2 catalytic and 2 regulatory)
  • cAMP binds to regulatory subunits of PKA—> these regulatory subunits then released from catalytic domains —> activated PKA
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39
Q

What is an example of the cAMP pathway and what occurs?

A

ADRENALINE INDUCING GLYCOGEN BREAKDOWN

  • Adrenaline binds and activated GPCR (sdrenergic) activates activated adenylyl cyclase and alpha subunit of protein
  • ATP —> cAMP –> active PKA –> activates enzymes specific to glycogen breakdown
  • then via ATP it forms active glycogen phosphorylase
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40
Q

In activation of gene trasncription via adrenaline through cAMP pathway, what is the pathway from active PKA?

A
  • Active PKA moves into nucleus (via pore) and binds to transcription regulaotrs–> leads to gene trasncription
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41
Q

Does active PKA have different cellular responsed based on cell type?

A
  • YES!!
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42
Q

What are G protein coupled receptors as drug targets?-

A

Adrenergic receptors (beta blockers) –> to decrease HR and contractility)

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43
Q

What is a treatment of cardiac aryhtmia and angina?

A
  • Inhibiting Beta adrengergic recpetor (GPCR) action
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44
Q

What does the drug inderal (proprananol) do?

A
  • Acts as a Beta 1 agonist

- competitively INHIBITS GPCR binding to NA–> slows heart contraction

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45
Q

What leads to cortisol secretion and what type of receptor pathay does this use?

A

ACTH

- ACTH is a GPCR

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46
Q

What is cushing syndromec and what is it associated with?

A
  • Chronic exposure to EXCESS glucocorticoids (steroids)
  • decreased growth in kids
  • Increased weight, hpertension, diabetes
  • osteoperosis, muscle weakness
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47
Q

What are potential causes in cushings syndrome?

A
  • Genetic Mutations in signalling pathway
48
Q

What can lead to changes in the level of cortisol secreted?

A
  • Mutations in any step of the pathway (cAMP signalling)
  • Pathway is overactive (cancer also has this overactive effect)
  • GPCR mutation
49
Q

What are the two types of activating mutations that occur in cushings syndrome?

A
  • Loss of function mutation (turns off protein) and gain of function (protein may be overactive)
50
Q

What occurs in mutation in regulatory protein?-

A
  • May not be able to turn off signalling pathway
51
Q

What occurs with a mutation in an enzyme that needs to be activated

A

Pathway may be blocked

52
Q

What are the key molecules in the phosphatidylnosol pathway?

A
  • GPCR–> G protein–> inositol phospholipid –> inositol 1,4,5 triphosphate–> PKC
53
Q

What are the key signalling molecules in the cAMP pathway?

A
  • GPCR activation –>G protein activation–> Adenylate cyclase activation–> ATP–> cAMP–> PKA activation
54
Q

Which two factors are responsible for directly activating Protein Kinase C (PKC)?

A
  • Diacylglycerol (DAG) and Ca2+
55
Q

What activates protein kinase A (PKA)

A
  • Cyclic AMP (cAMP)
56
Q

What does a loss of function mutation lead to?

A
  • Leads to INHIBITION of signalling pathway (symptoms like hormone deficiency)
57
Q

What does a gain of function mutation lead to?

A

Overactive pathway (symptoms similar to excess hormone or signalling molecule)

58
Q

Where can a loss or gain of function mutation occur?

A
  • ANY of the proteins involved in in GPCR signalling OR second messenger pathways
59
Q

What is cushings syndrome a result of ?

A

INCREASED cortisol secretion (adrenal cortex) OVERTIME

60
Q

How is cortisol normally produced and secreted?

A
  • CRH (corticotropin releasing hormone) in hypothalamus goes into hypophyseal system into ANTERIOR pituitary and acts on a GPCR to allow ACTH to be produced –> released into blood stream –> adrenal gland ACTH stimulates adrenal cortex cells to release and produce CORTISOL!
61
Q

What type of mutation occurs in cushings syndrome and which parts can be affected?

A
  • Gain of function mutation
  • overactive pathway
  • Alpha subunit of trimeric G protein
  • PKA
  • GCPR
62
Q

What are two gene mutation that lead to overactive /overexpressed receptor or G proteins or the catalytic subunit of PKA?

A
  • Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH)
  • Adrenal adenoma (tumors on adrenals gland)
63
Q

What are the gene mutations associated with primary pigmented Nodular Adrenocortical Disease (PPNAD)?

A

-Mutations in the catalytic or regulatory sub-units of PKA

64
Q

Which type of mutation can central hypothyroidism be and what does it lead to?

A
  • Loss of function mutation
  • mutation in Thyrotropin Releasing Hormone Receptor (TRHR) in anterior pituitary
  • Mutation causes inositol pathway to be INHIBITED
  • so thyrotropic cells can’t be stimulated from the TRH released from hypothalamus
  • SO NO production of TSH and no secretion of thyroid hormones
65
Q

What is the correct order for the release of thyroid hormones?

A
  • TRH released from HYPOTHALAMUS
  • TSH released from anterior pituitary
  • T 3 and T4 released from thyroid
66
Q

A loss of function mutation in cAMP PDE would result in?

A
  • Increased cAMP signalling due to inability to regulate duration of cAMP activation
67
Q

What does GEF (guanine nucleotide exchange factor) do?

A
  • Activates GTPase
  • Stimulates the release of GDP
  • GTP quickly binds–> GTPase activated–> GTP exchanged for GDP
68
Q

What does GAP do?

A
  • Gtpase Activsting Protein
  • hydrolyses GTP–> GDP
  • GDP remains tightly bound
69
Q

Which 3 are the most commonly phosphorylated as part of the enzyme coupled receptpr pathways?

A
  • Serine
  • Threonine
  • tyrosine
70
Q

Which part of the RTK is the part that is catalytic and can phosphorylate other molecules when activated?

A
  • Tyrosine kianse domain
71
Q

What does the insulin rercepotr exist in membranes as?

A

Dimeric form

72
Q

In general, what to RTK’s lead to when activated?

A
  • cell growth
  • cell division
  • proliferation/cell survival
73
Q

What do RTK’s prevent/inhibit?

A
  • Apoptosis
74
Q

How do receptor tyrosine kinases work?

A
  • Receptor in membrane is monomer
  • Ligand binds—> forms DIMER with a receptor of SAME family –> they can activate EACH OTHER (autophosphorylation) –> both receptors are activated
  • Then receptors can activate multiple pathways in the cell
75
Q

What do the phosphorylation points in the tail of the receptor (RTK pathway) provide?

A
  • Binding sites for different adapter molecules
76
Q

Which domains do proteins that are binding to ECF receptors have to have?

A
  • SH2
    SH3
    PTB
    PH
77
Q

What does SH2 recognise?

A
  • Phosphorylates tyrosine residues
78
Q

What does SH3 do?

A
  • Can bind to proline rich regions
79
Q

What does PTB recognise?

A
  • (Phospho Tyrosine Binding domain)

- Recognises Phosphorylated tyrosine residues

80
Q

What does PH recognise?

A
  • Hyperphosphorylated inositide molecules
81
Q

What are adaptor proteins?

A
  • Act like bridges from one protein kinase to another

- can form a bridge between molecules that don’t have their own SH2 or PTB domains e.g. Grb2

82
Q

What are scaffold proteins and what do they allow/reduce?

A
  • bring together multiple interacting signals/proteins so they can activate each other
  • CAUSES RAPID ACTIVATION
  • REDUCES other signal molecules from other pathways from interfering
83
Q

In cancer, what part of the RTK are looked at?

A
  • The phosphorylation sites

- Usually in cancer the phosphorylation sites can be overactive

84
Q

What does PI3K do and what is it activated by?

A
    • Recruited and activated by RTKs
  • Phosphorylates inositol phospholipids in plasma membrane
  • Becomes the docking site for intracellular signalling proteins (Akt) and activates them
85
Q

What is Akt also known as and what does it do?

A
  • PKB (protein kinase B)

- Promotes growth and survival (inhibits BAD–> BAD encourages apoptosis)

86
Q

What is BcI2? (pro or anti apoptotic)

A
  • Pro apaptotic
87
Q

What is Bad? (pro or anti apaptotic)

A
  • anti apoptotic
88
Q

What occurs in terms of Bad and BcI2 when Akt (PKB) is active ?

A
  • It phsophorylates Bad
  • Bad and BcI2 dissociate
  • So BcI2 is CTIVATED AND APOPTOSIS IS INHIBITED (SURVIVAL SIGNALS)
  • So Phosphorylation INIHBITS Bad
89
Q

What do tyrosine associated kinase receptors associate with?

A
  • Proteins that have tyrosine kinase activity (not the tyrosine kinases)
  • e.g. CYTOKINE RECEPTORS
90
Q

Which two families of proteins are important for tyrosine associated receptors?-

A
  1. Src (SARC) kinase family (associate with receptors)
  2. Janus Kinase family e.g. JAK 1, 2, TYK 2
    (signalling family receptors–> growth hormone receptors
91
Q

How are cytokine receptors formed?

A
  • Pre assembled with JAK protein on tail (has kinase function)
  • JAKs are Phosphoryltors –> they autophospohrylate each other –> JAKS phosphorylate cytokine receptor
  • STAT 1 and 2 recruited for transcription
92
Q

What do epidermal growth factors activate?

A
  • Receptor Tyrosine Kinases
93
Q

Which protein domains bind phosphorylated tyrosine residues?

A
  • PTB and SH2 (depends on individual affinity for which one actually binds)
94
Q

Janus Kinases activates which family of proteins?

A
  • STATs (src is also important)
95
Q

What do nuclear receptors allow for?

A
  • Transcription to be regulated!

- Reproduction, homeostasis, integrated metabolism

96
Q

What is the biggest class of hormones that bind to nuclear receptors?

A
  • Steroids

but also vitamin D and thyroid-less large

97
Q

What type of receptor does cortisol use?

A
  • A nuclear receptor becasue it is lipophillic
98
Q

What receptor can be targeted in cushings syndrome?

A
  • Glucocorticoid receptor (GR)
99
Q

What does the drug Mifepristore (RU486) do?

A
  • It is a GR and PR (progesterone receptor) antagonist (prevents signalling and activation)
  • Active in abortion
  • trialled in depression
100
Q

Where are steroid hormoens synthesised?

A
  • Adrenal, Overies and testes
101
Q

What can congenital adrenal hyperplasia result from?

A
  • Defficiencies in 1-hydroxylase
  • 11 beta hydroxylase
  • or 17 alpha hydroxylase or C17-20 lyase
102
Q

What are DNA binding sites called?

A
  • Hormone Response Elements (HREs)
103
Q

Steroid hormones bind to HREs as…..

A

HOMO DIMERS (GR, ER, PR, AR)

104
Q

RXR-NRs (Retinoid X receptors) bind to HREs as:

A
  • Heterodimers (e.g. RAR, PPAR )
105
Q

What do the estorgen receptors exist as?

A
  • Homodiemrs

- ER alhpa and ER beta receptors form the homodimer

106
Q

What is ERalpha important for?

A
  • Mediating estradiol effect (femaile reporoduction ,

mammary gland function, bone, CV system, brain

107
Q

What is ER beta im,portant for?

A
  • OVARY, bone, breast, brain ,

- different expression patterns

108
Q

What occurs in a ER alpha deficiency?

A
  • Resistant to estorgens (high estrogen blood levels)
  • Continued growth
  • Estrogen important for male and femalse bone formation
109
Q

What is CML and which pathway is an issue here?

A
  • Chronic Myelopid Leukemia (excess white blood cells)
  • overflow of immature leukocytes into bloodstream
  • OVERACTIVE INTRACELLULAR SIGNALLING PATHWAY (cell growth and survival)
  • oncogenic tyrosine kinase (BCR-ABL)
110
Q

What is the action of BCR-ABL in the overactive signalling pathway of CML?

A
  • This oncogenic tyrosine kinase phosphorylates kinases in the cell proliferation pathway (Ras/MAPk, PI3K/Akt, JAK/STAT)
  • This leads to uncontrolled cell growth
111
Q

What is a possible treatment of CML in terms of the oncogene BCR-ABL?

A
  • Gleevic (inhibitor)
112
Q

What is the action of Gleevic and what is it used as

?

A
  • binds to BCR-ABL binding site (so ATP can’t bind) and so no phosphorylation
  • Used as a possible treatment for CML
113
Q

What is the action of TKIs (Tyrosine kinase inhibitors) ?

A
  • Competitive inhibition of ATP and upstream or downstream substrate
114
Q

How do mAbs (monoclonal antibodies) work (in context of CML treatment)

A
  • They bind competitively with receptors ligand binding site (so can’t be activated or dimerise) (inhibit cell surface receptors)
115
Q

What is HER2, which family is it from, which protooncogene is it encoded by and what is a special feature of it?

A
  • Human Epidermal Growth Factor receptor 2
  • From the EGFR family
  • Encoded by proto oncogene ERBB2
  • Special feature: Can form heterodimers with other EGFR family members
  • Associated with breast cancer (aggressive)
116
Q

What does the HER2/EGFR do when active?

A
  • Activates the MAPK and PI3K pathways

- these pathways lead to cell growth and proliferation

117
Q

What is Heceptin and what action does it have?

A
  • Monoclonal antibody
  • Specific to HER2
  • binds to HER2 so it can’t activate the intracellular signalling pathway
  • Is a treatment for HER2 positive breast cancer

BMS2021 (7 decks)

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