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Dynamic Cell > Tyrosine kinase receptors > Flashcards

Tyrosine kinase receptors Flashcards

1
Q

3 main types of cell surface receptors

A

ion-channel linked

GPCR

enzyme-linked

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2
Q

which type of receptor are RTKs?

A

enzyme-linked

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3
Q

which molecule type signals via RTKs?

example

A

growth factors

epidermal GF
- stimulate differentiation, survival + proliferation

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4
Q

what can growth factor signalling influence?

A

‘growth’ (in cell size + no.)
at different levels:
cells, tissues, organs + body

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5
Q

insulin-like growth factors

A

IGF1 + IGF2 (ligands)

  • > IGF1R (receptor)
  • > growth

important in foetal development
- promote growth

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6
Q

effects of changes in IGFs

A

IGF1 knockout
= 60% normal size at birth

IGF1 mutation
= leprechaunism

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7
Q

RTK characteristics

A

cysteine-rich extracellular domain

single a-helix hydrophobic transmembrane domain

intracellular domain with tyrosine kinase activity + several tyrosine residues

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8
Q

RTK subfamilies

A

based on structural homology

all have cystine-rich domains on outside of cell

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9
Q

cysteine-rich domains on outside of cell allow…?

A

disulphide bonding of extracellular portion of receptor
-> to fold into correct shape to recognise signal w/ high specificity

can bind to low [signal] w/ high affinity

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10
Q

experiment to investigate RTK function

A

EGF introduced to cells
-> no response
.:. cells don’t respond to EGF w/out receptor

introduced plasmids via transfection

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11
Q

experiment to investigate RTK function

- different plasmids + effects

A

EGFR
-> EGF binding, protein phosphorylation, DNA synthesis + cell division

FGFR + control receptor
-> no response

EGFR + point mutation inactivates kinase
-> EGF binding but not kinase activity

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12
Q

receptor internalisation and degradation via lysosomes

A

form of adaptation/desensitisation to prolonged signal activation

can occur in absence of a functional TK domain

.:. receptor internalisation not part of signalling process

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13
Q

what is the sequence of responses after EGF is added?

A
  1. GF binding
  2. TK phosphorylation of proteins
  3. GF/receptor internalised, degraded
  4. new gene expression
  5. cell division
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14
Q

how does the signal cross the membrane?

A

ligand interacts with receptor w/ high affinity + specificity

  • > brings together 2 copies of receptor
  • > response
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15
Q

activation of PDGF-R

- proteins that form

A

PDGF
= 2 polypeptides encoded by 2 genes
- dimerise to form 3 proteins

A + A protein
- can homodimerise to form A-A protein

A + B can heterodimerise
= A-B protein

B + B can homodimerise
= B-B protein

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16
Q

activation of PDGF-R

- subunits

A

alpha receptor
- interacts with PDGF-A + PDGF-B

beta receptor
- interacts only with PDGF-B

17
Q

activation of PDGF-R

- depletion of alpha-receptors

A

A-A = a-a
= TK activity
-> DNA synthesis
(internalised + down-regulated)

A-B = beta
b-receptors don’t recognise A protein
-> 2 receptors not brought together
= no response

B-B = b-b
= TK activity
-> DNA synthesis
(internalised + down-regulated)

18
Q

activation of PDGF-R

- experiment 2

A

activating mutations
(kinase activity in absence of signal)
- in cancers (various RTKs)
- achondroplasia (FGFR3)

inactivating mutations
- dominant -ve mutations

19
Q

FGF signalling in anterior-posterior axis patterning

A

FGF-R over-expression
= suppressed head formation

FGF-R knock down
(point mutation inactive kinase)
= normal head development BUT no tail

20
Q

TK domain substrates

A

phospholipase C
Src
PI3-kinase
GAP

21
Q

TK domain substrates

- contain conserved binding motifs…

A

SH2 domain
- receptor interaction

SH3 domain
- interactions with other signalling molecules

22
Q

activation of RTKs

- autophosphorylation

A

1st phosphorylation involves kinase domain

-> raises kinase activity for subsequent phosphorylation events

23
Q

RTK activation of SH2/SH3 domain proteins

A

SH2 domains interact w/ regions of receptor
- where local structure is influenced by presence/absence of P group

-> changes conformation

= allows docking of specific substrates to specific regions of receptors

24
Q

RTKs as targets for new drugs

A

deregulation of RTK signalling
- crucial for development of hyper proliferative diseases e.g. cancer

> neutralising Abs bind + block signal

> prevent receptor dimerisation

> kinase inhibitors via binding to kinase domain

Dynamic Cell (15 decks)

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