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BIOC2003 > Signalling 2 > Flashcards

Signalling 2 Flashcards

1
Q

Outline a1 activation by adrenaline

A
  1. Gq activates PLC
  2. PLC cleaves PIP2 which increases DAG + IP3
  3. IP3 interacts with Ca2+ channels on ER and SR
  4. effects: calcium added to proteins + PKC
    - > prominent slow depolarising current
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2
Q

PKC characteristics

A
  • cytosolic protein
  • > increase cytosolic [Ca]2+ allows PKC to interact with membrane phospholipids
  • > contact with DAG activates PKC, allowing it to phosphorylate its target membrane
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3
Q

Outline calcium calmodium binding

A
  1. Cytosolic [Ca++] ~ 0.1uM -> increase 100 fold
  2. Ca++ binds to calmodium calcium sensor
  3. Conformational change in calmodium -> binds proetins
  4. CaM kinases phosphorylate their target proteins
  5. Calmodium can also be a protein domain
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4
Q

Points of amplification of a1

A
  1. Adrenaline:receptor complex is able to catalyse GTP:GDP exchange on multiple G-protein
  2. Each PLC can catalyse many IP3 and DAG’s
  3. Each activated Ca channel releases many Ca2+
  4. Each activated PKC can phosphorylate many membrane proteins
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5
Q

How to shut off a1 adrenaline stimulation?

A
  1. DAG is either hydroxylated or phosphorylated with an alcohol
  2. IP3 is converted to Inositol by phosphatases
  3. Calcium taken into ER by Na/Ca exchanger, Ca/ ATPase pump
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6
Q

Receptor Tyrosine Kinases

A

Dimers with E.C. hormone-binding domain + I.C. protein tyrosine kinase domain

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7
Q

Tyrosin kinase mech of action

A
  1. Upon membrane binding
  2. RTK monomers cross phosphorylate each other
  3. Phosphorylation RTK makes it a site of attachment for proteins with SH2 domains / PTB
  4. Localising proteins at memb.
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8
Q

How does insulin become fully active?

A

Phosphorylation of kinase

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9
Q

EGFR activation mech

A
  1. Binding EGF to each EGFR monomer induces structural charge
  2. Monomers dimerise
  3. Proximity of cytosolic domains allows cross phosphorylation
  4. Tyrosine phosphates act as docking sites for Grb-2, attached to sos
  5. Sos catalyses GDP -> GTP on membrane-bound Ras, activating it
  6. GTP: Ras binds and activates Raf a membrane bound protein kinase
  7. Series of protein kinases are phosphorylated + activated => phosphorylation of sacral TF’s altering activity
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10
Q

Grb-2

A

‘Adaptor protein’ = bridge to link proteins

-> composed of SH2 domain sandwiched between 2 SH3 domains

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11
Q

What do the different domains on Grb-2 do?

A

SH2 - binds sequences containing phosphorylated-Tyr

SH3 - binds proline-rich sequences

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12
Q

Sos

A

Guanine nucleotide exchange factor

-> catalyses GDP -> GTP on Ras protein when recruited to membrane via Grb-2

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13
Q

Ras

A

Small G-protein -> monomeric

-> slower GTPase activity than heterotrimeric

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14
Q

What do GAPs do

A

Increase GTPase activity by ~10^5 fold

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15
Q

Outline insulin receptor signalling

A
  1. Binding of insulin to dimeric receptor forces PTK domains together
    - > cross-phosphorylation
  2. Fully activates kinase activity -> more cross-phosphorylation
  3. Phosphorylated tyrosine residues act as docking sites for IRS-1 which gets phosphorylated
  4. Phosphorylated IRS-1 can bind PI-2K which now, located at mem phosphorylated PIP2
  5. PIP3 made from PIP2
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16
Q

PIP3 effects

A

Allows PPK1 + PKB -> associate with membrane via pH domains

-> phosphorylated PKB dissociates from memb. + phosphorylated target proteins

17
Q

IRS-1

A

Phosphorylated on several tyrosine residues

-> IRS-1 already associated with membrane due to pH domain which can bind PIP2

18
Q

What happens when IRS-1 is phosphorylated

A

Dissociate from insulin receptor

19
Q

Docking protein

A

Can bind many proteins including Grb-2 (MAPK pathway)

20
Q

How can insulin response be short and long?

A

Other proteins e.g. IRS-2 can assemble at phosphorylated insulin receptor
-> simultaneous stimulation of neurons for short + long term

21
Q

Which proteins bind PIP3 and what are the effects?

A
  1. PDKA 1 via PH domain -> localises it to memb+ activates it
  2. PKB via PH domain -> phosphorylated + activated by PDK1
    - > phosphorylates several proteins in both cytosol + nucleus
22
Q

Insulin points of amplification

A
  1. Insulin receptor can phosphorylate multiple IRS-1 proteins
  2. PI-3K can catalyse formation of multiple PIP3 molecules
  3. PDK1 catalyses formation of multiple PKB enzymes
  4. PKB can go on to phosphorylate many proteins
23
Q

How are insulin receptors shut down?

A
  1. Lipid phosphatases, recruited by active insulin receptors, dephosphorylate PIP3
  2. Insulin activates protein phosphatase 1 which counteracts PKA actionm inhibiting PP1
    - > stimulated by glycogen + AD

BIOC2003 (13 decks)

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