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BIOL 2020 > 7: Cell Signalling And Transduction > Flashcards

7: Cell Signalling And Transduction Flashcards

1
Q

Second messengers

A

Small non-protein molecules that relay a signal to the interior of the cell

  • cAMP
  • IP3
  • DAG
  • Ca2+
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2
Q

Basic signalling pathways

A
  • GPCRs
    • activate G proteins which then kick off a cascade, involving second messengers (cAMP, IP3)
  • Receptor kinases
    • kinases
    • when they bind a ligand their kinase activity is activated and they kick off a phosphorylation cascade
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3
Q

GPCRs

A
  • huge family of proteins
  • 7 transmembrane domains (a helices)
  • named because they activate heterotrimeric G proteins
  • contain a variable region for ligands to bind on cytosolic side of membrane
  • GTPases
    • attached to GTP = ON
    • Attached to GDP = OFF
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4
Q

GTPases

A
  • GTP = ACTIVE
  • GDP = INACTIVE
  • category 1
    • monomeric and small
    • ran, ARF, Sar 1
  • category 2
    • trimeric (3 subunits)
    • a and g secure the G protein to the plasma membrane
    • peripheral membrane proteins
    • have small hydrophobic domain (can move around membrane)
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5
Q

GPCR mechanism

A
  1. Resting state
    • receptor not bound to ligand
    • Ga is bound to GDP and associated with GBY
  2. Ligand binds receptor
    • Ga releases GDP and acquires GTP (active)
  3. Ga and GBY subunits separate
    • Ga leaves
  4. G protein subunits activate or inhibit target proteins
    • imitates signal transduction events
    • target protein = effector protein
  5. Ga subunit hydrolyzes its bound GTP to GDP
    • now inactive
    • target protein also inactivated
  6. Subunits recombine to form an inactive G protein
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6
Q

Terminating GPCR response

A
  1. GRK (G protein receptor kinase) phosphorylates the GPCR
  2. Arresting binds the phosphorylated GPCR (now inactive)
  3. Arrestin recruits AP2
  4. AP2 recruits a clathrin coat
  5. GPCR is internalized by endocytosis
  6. GPCR in the endosome may have several fates
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7
Q

Adenylyl Cyclase

A
  • makes cAMP from ATP
    • removes to phosphates and creates rung structure
  • after ligand binds GPCR, G protein is activated, Ga subunit activates adenylyl cylase
    • adenylyl cyclase makes cAMP
    • GTP on Ga is hydrolyzed
    • Ga dissociated from adenylyl cyclase so no more cAMP
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8
Q

cAMP

A
  • second messenger with many roles
  • phosphodiesterase (PDE) will shut down signal
    • convert cAMP to AMP
  • main target is PKA (protein kinase A)
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9
Q

PKA

A
  • has 2 catalytic subunits (kinase activity) and 2 regulatory subunits (structural)
  • regulatory subunits normally bind to catalytic subunits (inactive form)
  • cAMP binds to the regulatory subunits of PKA and catalytic subunits are released
  • catalytic subunits now available to phosphorylate/activate
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10
Q

Fight or flight response

A
  • mediated by cAMP/PKA
  • PKA turns on transcription factors by going into nucleus and phosphorylation gets CREB
    • also liberate glucose for use in muscles
    • glycogen turned into glucose
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11
Q

PLC

A
  • phospholipase C
  • makes lipid derived second messengers
    • IP3 and DAG
  • phosphotidylinositol with phosphates on inositol ring = PIP2
  • PLC will cleave PIP2 into IP3 + DAG
  • if a protein has a PH domain it will bind to PIP2
    • PLC has a PH domain
    • PLC will bind to PIP2 and cut it into IP3+DAG
    • cuts between phosphate and glycerol
  • IP3 made up of the phosphate+inositol
  • DAG is the diagylglycerol tail
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12
Q

PLC mechanism

A
  1. Ligand binds GPCR
    • activates the G protein
  2. Ga stimulates PLC
    • PLC cuts PIP2
  3. DAG remains in the membrane
  4. IP3 released into cytosol
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13
Q

IP3 and DAG

A
  • DAG stays in membrane and activates PKC

- IP3 goes into cytoplasm and binds IP3 receptors on ER to release Ca2+

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14
Q

Calcium

A
  • second messenger
  • released by SER by IP3
  • concentration of Calcium in SER is 10,000x higher than in cytoplasm
  • once cell filled with calcium, ATP driven pumped will pump it back into SER
  • need DAG and Ca2+ for PLC activation
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15
Q

Calmodulin

A
  • calcium binding protein
  • contains 4 binding sites
  • has very low affinity for calcium, so it is only activated when calcium concentration is VERY HIGH
  1. Calmodulin binds 4 calcium ions
  2. Calmodulin changes conformation, resulting in active complex
  3. The 2 globular hands of the complex wrap around a binding site on a target protein
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16
Q

Calcium release following fertilization of animal egg

A
  1. Blocks polysperm
    • exocytosis of vesicles to change coat proteins so that no other sperm can fuse
  2. Egg activation
    • resumes metabollic pathways after floor of Ca2+
    • ripple effect of calcium
17
Q

Receptor kinases

A
  • when they bind a ligand their own kinase activity is stimulated and starts a phosphorylation cascade
  • pathway often involved in growth
    • ligand is often a growth factor
    • involved in mitosis
18
Q

Tyrosine kinases

A

-activated by phosphorylation on a tyrosine residue

19
Q

Serine/threonine kinases

A

-activated by phosphorylation on a serine/threonine residue

20
Q

RTKs

A
  • receptor tyrosine kinase
  • has a binding site for ligand on outside
  • single transmembrane domain (a helix)
  • tyrosine amino acid residues on cytoplasmic portion
21
Q

RTK mechanism

A
  • once the ligands bind, 2 receptors cluster together
  • AUTOPHOSPHORYLATION: each receptor puts phosphates on its neighbouring receptor
    • receptor kinase now active
  • proteins with SH2 domain can now bind to phosphorylated tyrosines (to become phosphorylated)
    • eg. GRB2
22
Q

Ras

A
  • small, monomeric G protein
  • anchored at inner surface of plasma membrane by lipid group
  • Ras-GTP = ON
  • Ras-GDP = OFF
  • when ras is on, it will lead to cell proliferation
  • SOS is the GEF (guanine exchange factor) for Ras (to activate it)
23
Q

Ras mechanism

A
  • receptor kinase activates GRB2 (which has SH2 domain)
  • GRB2 activates SOS
  • SOS puts GTP on Ras
  • Ras is activated
  • Ras triggers extensive phosphorylation cascade (Ras-MAP pathway)
24
Q

Ras-MAP pathway

A
  • Ras phosphorylates Raf (MAPKKK)
  • RAF phosphorylated MEK (MAPKK)
  • MEK phosphorylates MAPK
  • MAPK goes into nucleus and turns on transcription factors (eg. Ets and Jun)
    • turning on genes involved in cell proliferation

-a GAP will then turn off Ras

  • all members of this pathway can cause cancer when mutated
    • mutation in gene results in no responding to on/off signalling
    • 30% of all cancers have something wrong in this pathway
25
Q

Proto-oncogenes

A

-genes that have the potential to become cancer causing

26
Q

Cross-talk in signalling

A
  • pathways not linear
  • interconnected web
  • components of one pathway participate in other pathways

BIOL 2020 (8 decks)

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