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MCG Review > RK Lectures 5-8: Principles of signal transduction/G-protein-coupled receptors/Receptor protein-tyrosine kinases > Flashcards

RK Lectures 5-8: Principles of signal transduction/G-protein-coupled receptors/Receptor protein-tyrosine kinases Flashcards

1
Q

What ligands work with G-protein coupled receptors?

A

neurotransmitters (epi, serotonin, dopamine)
histamine
sensory stimuli (light, odorants)
many prescription drugs

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2
Q

Describe the receptors of G-protein coupled receptors.

A

proteins with 7 transmembrane domains
bind ligand extracellularly and cause a conformational change in the receptor allowing for the intracellular domain to interact with a heterotrimeric G-protein

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3
Q

Describe the structure of heterotrimeric G-proteins.

A

3 subunits (alpha, beta, gamma)
beta and gamma subunits always found together
alpha subunit binds GTP and hydrolyzes to GDP

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4
Q

How are heterotrimeric G-proteins activated?

A

begin with in inactive form (all three subunits together, alpha bound to GDP)

  1. ligand binds
  2. receptor adopts conformation allowing interaction with the alpha subunit
  3. alpha subunit releases GDP and binds GTP
  4. alpha-GTP dissociates from beta-gamma
  5. alpha-GTP is the active form and can interact with downstream effectors (must interact because it has poor GTPase activity on its own and needs to hydrolyze the GTP)
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5
Q

Describe the inactivation of heterotrimeric G-proteins.

A

after alpha-GTP activates its target protein and hydrolyzes to alpha-GDP it becomes inactive and reassociates with the beta-gamma subunit

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6
Q

List the downstream effectors for heterotrimeric G proteins.

A

Gs
Gi
Gq
Gt

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7
Q

Describe the chain of events that occur when the downstream effector Gs is activated by a heterotrimeric G protein.

A

activation of adenylyl cyclase (via its alpha subnit)
conversion of ATP to cAMP which can activate targets such as PKA (dissociation of regulatory subunits x2 from active catalytic subunits x2)
phosphorylation of targets (glycogen phosphorylase and glycogen synthase)

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8
Q

Describe the chain of events that occur when the downstream effector Gi is activated by a heterotrimeric G protein.

A

inhibition of adenylyl cyclase

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9
Q

Describe the chain of events that occurs when the downstream effector Gq is activated by a heterotrimeric G protein.

A

activates phospholipase Cbeta

breaks down membrane phospholipid PIP2 into IP3 and DAG

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10
Q

What does IP3 do?

A

activates the release of calcium inside the cell which activates PKC
many other signaling functions

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11
Q

What does DAG do?

A

directly activate PKC

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12
Q

Describe the chain of events that occurs when the downstream effector Gt is activated by a heterotrimeric G protein.

A

activated by rodopsin receptor
activates cGMP phosphodiesterase
breaks down cGMP

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13
Q

Which diseases inhibit heterotrimeric G-proteins?

A

cholera

pertussis

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14
Q

What does cholera toxin do to the body?

A

ADP-ribosylates the alpha subunit of Gs so that it can no longer catalyze hydrolysis of GTP to GDP leading to perminently active alpha subunit
results in prolonged rises in cAMP levels and activation of PKA
in the intestinal epithelium this results in efflux of Cl- of water resulting in copious, watery diarrhea

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15
Q

What does pertussis toxin do to the body?

A

ADP rybozylates alpha subunit of Gi preventing binding to GPCRs preventign activation
causes whooping cough

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16
Q

List some of the possible ligands for Receptor Tyrosine Kinases (RTKs).

A

platelet-derived growth factor
epidermal growth factor
fibroblast growth factor
insulin

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17
Q

Describe the steps of initiation of the signal transduction for Receptor Tyrosine Kinases (RTKs).

A
  1. binding of ligand to single-pass transmembrane protein receptors allowing for dimerization
  2. auto/trans phosphorylation
    3a. activation of receptor’s catalytic function
    3b. creation of site for target protein recruitment
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18
Q

Outline the MAP Kinase cascade.

A
  1. activation of RTK
  2. binding of Grb2 (which is constituively bound to SOS via its SH3 domain) to RTK via SH2 domain
  3. SOS activates Ras
  4. Ras activates Raf
  5. Raf (a serine/threonine kinase) phosphorylates MEK
  6. MEK (a MAPKK) phosphorylates ERK (a MAPK)
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19
Q

What is Ras?

A

a small G-protein which can bind GTP (active state) and GDP (inactive state)
has GTPase activity

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20
Q

Describe the cycle of guanine neucleotides with small G proteins.

A

small G-proteins bound to GDP are in the inactive state
Guanine nucleotide exchange factors (GEFs) cause them to dissociate so that small G-proteins can bind GTP which puts them in their active form
GTPase activating proteins (GAPs) accelerate the rate of GTP hydrolysis by small G-proteins and thereby inactivate them

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21
Q

Outline the Phosphatidylinosital-3 kinase (PI-3K) pathway.

A
  1. p85 regulatory subunit binds active RTK
  2. p110 catalytic subunit phosphorylates the 3 position of the inositol ring on PIP and PIP2 (activating it)
  3. these then activate (indirectly and directly) Akt/PKB (ser/thr kinase)
  4. phosphorylates substrates that promote cell survival and inhibit programmed cell death
  5. PTEN (tumor suppressor) dephosphorylates PIP and PIP2
22
Q

What is the structure of PI-3K?

A 
regulatory subunit (p85) with an SH domain
catalytic subunit (p110)
23
Q

Describe the relationship between RTKs and cancer.

A

human cancers often have mutations in…
RTKs, Ras, or BRaf
(drives activation of the pathway in the absence of growth factors)
PI-3K pathway (constitutive activation of the pathway)

24
Q

What are the ligands for the Cytokine receptors pathway?

A 
prolactin
growth hormone
interferons
erythropoietin
etc.
25
Q

What is the difference between RTKs and Cytokine receptors?

A

RTKs: single polypeptide with intracellular portion containing intrinsic tyrosine kinase activity
Cytokine receptors: single polypeptide with intracellular portion that has NO catalytic activity or tyrosine kinase activity

26
Q

Describe the steps of signal transduction for Cytokine Receptors.

A
  1. binding of ligand to facilitate dimerization of two receptor subunits
  2. non-receptor tyrosine kinases (JAK) associated with the intracellular portion (constitutively bound) cross-phosphorylate to activate each other
  3. phosphorylation of intracellular portion of the Cytokine receptor allowing it to bind SH2-containing proteins (STAT proteins) that are transcription factors
  4. dimerization of activated STAT proteins (pY of one STAT binds the SH2 of its dimeric partner and vice versa)
  5. translocation of the STAT dimer to the nucleus where it binds DNA to activate expression of specific genes
27
Q

What kind of receptors are found in the TBFbeta/BMP pathway?

A

receptor serine/threonine kinases

28
Q

What roles does the TGFbeta/BMP pathway play?

A

embryonic development
wound healing
disease-related fibrosis
cancer

29
Q

Describe the general steps of signal transduction for the TGFbeta/BMP pathway.

A
  1. TGFbeta ligands induce type I and II receptors to dimerize
  2. Type II receptors are constitutively active but upon ligand-induced dimerization they phosphorylate type I receptors
  3. Activation of Type I receptor’s kinase activity which can phosphorylate SMAD factors (their major substrate)
30
Q

Describe the pathway of SMADs.

A
  1. R-SMAD (receptor-SMADs) are phosphorylated by Type I TGFbeta receptors
  2. R-SMAD dimerizes with co-SMAD (not phosphorylated by the receptor)
  3. R-SMAD/co-SMAD dimer enters the nucleus to activate expression of specific genes (their function can change if it is not a TGFbeta receptor that has phosphorylated it)
31
Q

Describe the ligands and receptors involved in the Notch pathway.

A

Receptor: Notch proteins
Ligands: Delta or Jagged
both ligand and receptor are single pass transmembrane proteins

32
Q

Describe the steps of signal transduction for the Notch pathway.

A
  1. Notch expressing cell comes into direct contact with Delta or Jagged expressing cell (contact-dependent signaling) so that Notch becomes bound to its ligand
  2. Notch’s intracellular domain (NICD) is proteolytically cleaved
  3. NICD migrates to the nucleus
  4. interacts with DNA-CSL (binding factor)
  5. complex binds transcriptional co-activators to turn on expression of target genes
    * note that unbound CSL inhibits expression of Notch pathway target genes
33
Q

What critical roles does the Notch pathway play?

A

embryonic development

cancers

34
Q

What are the components of the signaling complex for the Wnt pathway?

A

Frizzled and LRP5/6

35
Q

What are the ligands for the Wnt pathway?

A

a large family of secreted proteins that have a covalently attached fatty acid

36
Q

Describe the steps of the Wnt pathway in the absence of Wnt ligand.

A

a complex of proteins (APC complex) in the cytoplasm leads to the proteolytic destruciton of beta-catenin
kinases phosphorylate beta-catenin (target it for proteolytic degradation by the ubiquitin-proteosome system)

37
Q

What is the composition of the APC complex?

A 
scaffold proteins (APC and Axin)
ser/thr kinases (CK1 adn GSK2beta)
38
Q

How is the Wnt pathway inhibited?

A

DNA-binding factors TCF/LEF in the nucleus

39
Q

Describe the steps of the Wnt pathway in the presence of Wnt ligand.

A
  1. Wnt binds to frizzled-LRP5/6
  2. Axin binds to LRP5/6 (disrupting the APC complex) AND Dvl binds Frizzled
  3. inhibition of Ck1 adn GSK3beta
  4. beta-catenin no longer exists in the phosphorylated state and is stabilized
  5. stable beta-catenin migrates to the nucleus and interacts with TCF/LEF and transcriptional co-activators to activate expression of Wnt pathway target genes
40
Q

How is the Wnt pathway post-translationally regulated?

A

secreted Wnt inhibitory proteins including…
SFRP (soluble Frizzled-related protein)
WIF1 (Wnt inhibitory factor 1)

41
Q

What is the secondary role of beta-catenin?

A

binds intracellular region of cell-cell adhesion molecules (cadherins) to help tether them to the actin cytoskeleton to provide stability to cell-cell junctions

42
Q

What critical roles does the Wnt pathway play in the body?

A

embryonic development
regulator of stem cells in homeostatic maintenance of adult tissues
cancers (colorectal cancer specifically)

43
Q

Describe how a mutation in the Wnt pathway causes cancer.

A

mutations in APC cause Adenomatous polyposis coli (Familial Adenomatous Polyposis)
lacking APC causes beta-catenin to be constituatively stable so the pathway is continually on
similarly, mutations that stabilize beta-catenin also result in the pathway being continually on
APC is a tumor suppressor gene
beta-catenin is a proto-oncogene

44
Q

Describe the receptors and ligands for the Hedgehog pathway.

A

Receptor: Patched (Ptch1)
Ligands: HH (small family of secreted proteins)

45
Q

Describe the activity of the Hedgehog pathway in the absence of ligand.

A

Ptch1 functions to inhibit signaling activity of Smoothened (Smo; a second plasma membrane protein) catalytically (mechanism unproven)
in the absence of Smo activity Gli (the pathway responsive transcription factor) is phosphorylated by PK, CK1, and GSK3beta
proteolytic cleavage into GliR (Gli-repressor)
entrance of GliR into the nucleus to inhibit target gene expression

46
Q

Describe the activity of the Hedgebod pathway in the presence of ligand.

A
  1. HH binding to Ptch1 relieves inhibition of Smo
  2. Smo signals (poorly understood mechanism) to prevent the phosphorylation and proteolytic cleavage of Gli
  3. Full length, activated GliA enters the nucleus
  4. Activation of expression of HH pathway target genes
47
Q

Where is most of the HH pathway localized?

A

the primary cilium (a microtubule-based organelle)

48
Q

What critical roles does the HH pathway play?

A

embryonic development
regulator of adult stem cells
some diseases ( Ptch1 is a tumor suppressor gene)

49
Q

What is Gorlin syndrome?

A

mutations in Ptch 1 resulting in constitutive HH signaling

predisposes individuals to basal cell carcinoma (skin) and meduloblastoma

50
Q

What is holoprosencephaly?

A

common and devastating birth defect that includes cyclopia

caused by mutations in SHH or ingestion of cyclopamin during pregnancy (which inhibits Smo)

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