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343 - Biochemical Signalling > 3 - Single Pass Receptors - Gray > Flashcards

3 - Single Pass Receptors - Gray Flashcards

1
Q

give 4 examples of single pass receptors

and briefly describe their structure

A
  • guanylate cyclase receptors eg atrial naturetic peptide
  • TGFB receptor family
  • receptor tyrosine kinase family eg insulin, growth factors
  • non-catalytic eg cytokine Rs
  • single TM helix that has its own enzyme activity or is coupled to another molecule that does. cannot act as own therefore function as dimers
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2
Q

briefly describe guanylate cyclase receptors as a whole

A

bind ligands and dimerise
intrinsic enzyme activity
converts GTP -> cGMP (2nd messenger) + PPi

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3
Q

Give an example of a guanylate receptor and its role in the body

A
  • eg atrial naturetic peptide receptor has guanylate cyclase activity
  • overall aim is to reduce blood volume
  • the ANP hormone secreted by heart muscle cells that are stretched (indicative of high blood pressure)
  • ANP binds to vascular smooth muscle cells causing them to relax
  • also causes kidney to excrete > water and sodium
  • overall acts to decrease venous return to the heart therefore decreasing blood pressure
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4
Q

Describe how a guanylate cyclase receptor generates a 2nd messenger. draw a diagram

A
  • binding of ligand eg ANP at extracellular surface causes dimerisation of the receptors
  • activates the guanylate cyclase domain which in turn activates the cGMP protein kinase allowing for the conversion of GTP -> cGMP (2nd messenger) and PPi
    343 2b
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5
Q

soluble guanylate cyclase is a ___ for other ___

A

receptor

ligands

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6
Q

which residues do kinases P in eukaryotes?

A

tyrosine or Ser/Thr residues

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7
Q

what are the role of kinases? name some substrates of kinases

A

can activate/deactivate other proteins
many kinases that have been P lead to kinase cascade
- substrates= receptors, microtubules, transcription factors, enzymes

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8
Q

describe what enzymes remove P groups and state how these are regulated

A

phosphatases remove P groups from substrates

they themselves can be Phosphorylated allowing regulation

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9
Q

What TF does TGFB effect? where does this activation take place?

A

TGFB Phosphorylates smads in the cytosol and allows them to move into the nucleus

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10
Q

What are TGFs? How does TGFB R result in the P transcription factors (draw a diagram of this)

A
  • TGFs small peptides released by proteolysis involved in paracrine / autocrine signalling. normally work to inhibit cell growth and division
  • receptor dimerisation (in conjunction with other receptor like proteins) phosphorylates the smad TF
  • ser P unmasks a Nuclear localisation sequence and SMAD moves into the nucleus
  • altering gene expression to inhibit cell proliferation
    343 - 2b word
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11
Q

In more detail, describe what happens when TGFB R binds its ligand. draw a diagram

A
  • its ligand is TGFB
  • binding of TGFB by type II receptor promotes dimerisation
  • T II recruits and phosphorylates Type I receptor
  • TI receptor Ps receptor - regulated SMADs (R-SMADs)
  • ## R-SMADs involved in differentiation, proliferation, activation of immune cells (eg T cell activation in INFLAMMATORY response)
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12
Q

What is the result of defects in TGF signalling?

A

common in cancers

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13
Q

Give an example of a TGFB molecule and explain how it is used in the medical world

A

bone morphogenic protein

  • used in implants to strengthen bones after fracture
  • BMPs play role in postnatal bone formation and heart, neural, cartilage formation
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14
Q

give an example of a receptor with no intrinsic enzyme activity

A

tyrosine kinase linked cytokine receptor

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15
Q

summarise the activity of the enzyme linked single pass receptors. draw a diagram

A
  • receptor itself does not have intrinsic enzyme activity
  • tightly couples with a protein kinase (eg tyr kinase)
  • ligand binding to receptor dimer causes activation of the cytosolic kinase. causes cross P and activation of the bound kinase
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16
Q

give some examples of cytokines and their functions within the body

A

INTERFERONS; interfere with viral replication
INTERLEUKINS; T cell activation
ERYTHROPOIETIN; increases production of RBC precursors therefore increasing overall no. RBCs in blood

17
Q

Describe cytokine R activation. draw a diagram to show this

A
  • binding of L, promotes dimerisation of the receptor (2 monomers are initially close together but Brought further together)
  • crossP of the cytosolic JAK kinase domains on activation lip -> conformational change allowing further P of tyr residues on the receptor
18
Q

Give a summary (with a diagram) of the JAK STAT pathway

A
  • STAT TF binds to the Phosphotyrosine residues on receptor via its SH2 domain. JAK causes P of STAT
  • phosphorylated STAT dissociates and dimerises @ SH2 domain
  • dimerisation exposes the NLS and STAT moves into the nucleus where it binds to DNA and activates transcription
  • phosphatase inactivates JAK and stops the signal
19
Q

Describe the SH2 domain

A
  • src homology 2 domain
  • conserved domain of around 100 aa
  • binds to P Tyr residues 1000x more strongly than normal Tyr residues
  • over 100 SH2 containing proteins in animals. not found in yeast/plants
20
Q

What is leptin? give an overall description of functions etc

A

leptin - “satiety hormone”

  • produced by adipose tissue and inhibits hunger. acts on the brain leading to decreased food intake
  • similar to interleukins and signal via cytokine receptor and JAK/STAT
21
Q

Describe briefly how RTK with intrinsic kinase activity stimulate a signal transduction cascade

A
  • ligand binding promotes receptor homo/hetero dimerisation
  • cross p of activation lip of cytosolic kinase domains -> activation of tyr kinase activity
  • further P of R creating docking points for binding of adapter proteins and initiation of signal transduction cascade
  • leading to changes in cell physiology and or gene expression
22
Q

Describe the class of RTKs and what they bind

A
  • largest family of cell surface receptors
  • major class of Rs for peptide hormones eg growth factors, insulin
  • many identified through cancer studies (because bind GFs)
23
Q

Name 2 different ligands for RTKs and state their differences in dimerisation
(draw diagrams)

A

HUMAN EPIDERMAL GROWTH FACTOR 1;
- binding of this EGF to monomers promote dimerisation through causing a conformational change
- binding of EGF causes 2 loops to further extended and interact with the other loop belonging to a separate monomer therefore promoting their dimerisation -> activation
INSULIN;
- already dimerised receptor is activated through binding of insulin

24
Q

Give a summary of the human epidermal growth factor receptors

A
  • 4 types of HERs which often act as heterodimers
  • HER2 in active loop conformation (doesnt need to bind L) and binds to HER1,3,4
  • HER2 gene amplified in 25% breast cancers therefore increasing signalling via ANY HER
25
Q

name a treatment for breast cancer and state its mode of action. draw a diagram outlining its action

A
  • Herceptin mAb binds to HER2 and prevents its dimerisation therefore blocks downstream signalling and proliferation of cells
  • immune cells targeted to tumour cells bring HER2 to the cell
26
Q

What is the difference between RTKs and cytokine receptors?

A
  • RTKs have a kinase domain as PART of their intracellular cytosolic domain
  • cytokine receptors require an additional kinase domain attached to their intracellular domain. it is not a natural part of the protein
27
Q

Describe (in more detail) the activation of RTKs. draw a diagram

A
  • dimerisation
  • protein kinase of each R initially P particular Tyr residues in the cytosolic kinase domains of its R partner.
  • transP on the activation lip of the kinase domains results in enhancement of their activation (they are never INACTIVE, but become > active on binding P)
  • enhanced kinase activity further P Tyr residues on the receptor
  • P Tyr residues of the Receptor act as docking sites for further adapter proteins that facilitate signal transduction
28
Q

How are RTKs inactivated? Give an example of where see inactivation. draw a diagram

A
  • RTKs undergo endocytosis and are then either degraded or recycled
  • endocytosis of the HER1 receptor is increased 10fold on EGF binding and > likely to be degraded
  • Rs that are bound and more likely to be degraded and unbound Rs are more likely to be recycled back to cell surface
29
Q

why is RTK inactivation important?

A

prevents prolonged cellular signalling

30
Q

What is the function of an adapter protein? give an example of a complex containing an adapter protein

A

link activated RTKs to other signalling proteins

eg GRB2 - SOS - inactiveRas GDP

31
Q

describe how we get activation of downstream signalling from an activated RTK, draw a diagram of the complex that forms

A
  • adapter protein GRB2 containing SH2 and SH3 domains couple the activated R to other signalling proteins
  • SH2 domain binds to phosphotyrosine residues
  • SH3 domain (60 aa - small protein) binds to proline rich regions of proteins
  • eg on the GEF (guanine nucleotide exchange factor) SOS
  • brings SOS to the membrane so it can then bind and activate Ras (Ras already present at membrane but SOS binding recruits it to the receptor complex)
32
Q

Draw a diagram showing Ras cycling between active and inactive forms to regulate a kinase cascade. Explain it as well

A
  • GEF (SOS) helps to activate Ras
  • RasGDP = INACTIVE, Ras GTP = ACTIVE
  • GEF promotes dissociation of RasGDP and GTP binds
  • RasGTP dissociates from its GEF and can then activate a signal transduction pathway. Ras activates a ser thr kinase (eg Raf) which activates a cascade of 3 sequentially activating kinases
  • MAPK (once activated) can then move into the nucleus to active tf (eg Myc)
  • Ras has inherent GTPase activity (binding of a GAP - GTPase activating protein enhances this activity) and inactivates itself -> RasGDP therefore turning off signal
33
Q

What is Ras?

A
  • Ras is an oncogene, often found deregulated in cancers

- also a small monomeric G protein found attached to the membrane

34
Q

some cell types have Ras ____ RTK linked signalling

eg _____

A

independent

eg EGF R can activate PLC

343 - Biochemical Signalling (16 decks)

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