EGFR Flashcards
Different EGFR isoforms and their ligands + role in cancer
Monomers that dimerise: EGFR, HER2, HER3, HER4
EGFR has ligands EGF, TGF-a, epiregulin, HB-EGF
HER 2 has no known ligand
HER3 nas neuregulin-1 and neuregulin 2
HER4 has neuregulin 1-4 and HB-EGF
EGFR homodimer and the HER2/3 dimer have been implicated in cancer, through MAPK and PI3K-Akt pathways.
EGF ligands and their signalling mechanisms
EGF, TGFa, HB-EGF, amphiregulin (AREG), epiregulin (EREG), epigen (EPGN), and betacellulin (BTC).
They are all synthesised from 1 TM precursors
They signal through autocrine (ligand released from cell and acts on same cell), paracrine (acts on adjacent cell), and juxtacrine (when the noncleaved TM ligand acts on an adjacent cell) mechanisms
AREG, EGF, TGFa, and HB-EGF can be packed into EC vesicles (exosomes), which can be taken up by neighbouring cells to initiate signalling.
Agonist binding induces a conformational change that initiates dimerisation. HER2 has no ligand - always can dimerise.
HB-EGF mechanisms and signalling
Heparin-binding EGF-like growth factor is released from membrane bound pro-ligands via catalysis by metalloproteinases or A distintegrin and metalloproteases (ADAMs)
Acts as a mitogen and chemotactic factor at fibroblasts and SM cells.
It acts on HER1 and HER4.
It can be bound to heparin sulphate proteoglycans for juxtacrine signalling mechanisms.
Dimer subtype configurations and features
Can form EGFR homodimer, HER2/EGFR, HER2/HER3, HER2/HER4, and a HER2 homodimer.
HER3 has no kinase domain.
EGFR and HER2/EGFR can signal through the Ras-Raf-MEK-MAPK pathway
All except EGFR homodimer can signal through PI3K-Akt pathways
Role of mutations in the EGFRs in cancer and examples + pharmacological implications
EGFR overexpression associated with NSCLC (60%).
EGFR mutations include L858R and L861Q in the activation loop.
E746-A750 is a deletion that increases kinase activity.
T790M increases affinity for ATP and decreases affinity for competitive inhibitors. Resistance to gefitinib, erlotinib, and lapatinib (type II).
R84K mutation in the EC domain of EGFRs in glioblastomas prevents the discrimination between signalling of different EGFR ligands - e.g., full signalling from EREG.
Mechanism of activation of the kinase domain
Activated by allosteric interaction between the C-lobe (activator) and N-lobe (receiver) of two dimers. Destabilises the autoinhibtory interactions in the activation loop of the receiver.
The C-lobe of one of the kinases then pushes the alpha-helix C on the N-terminal lobe of the other towards the active site.
This can still be done by HER3 despite not having a kinase domain.
EGFR signalling pathways
Can signal through PI3K-Akt, PLC-gamma, and Ras-Raf-MEK-MAPK to alter gene expression.
In order to signal through the Ras-Raf-MEK-MAPK pathway, it must be initiated by Grb2. Grb2 contains SH2 domains which interacts with the phosphotyrosines. It also contains a SH3 domain which will then mediate the continuation of the signalling downstream.
Other roles of EGFR in cancer and some treatments
HER2 overexpression is associated with increased breast cancers risk and aggression. Also involved in gastric ovarian, and salivary gland tumours.
Trastuzumab (antibody for the EC subdomain IV), pertuzumab (antibody for EC subdomain II) - prevents dimerisation, and lapatinib (type 2 RTK inhibitor) are inhibitors of HER2
HER3 is found to be over expressed in mammary tumours and overexpression of the HER3 ligand heregulin has been associated with increased tumour formation.
Role of the ligand in the stability and signalling of the EGFRs
Whether there is single ligand bound, symmetric ligands, bound, or asymmetric ligands bound.
Single ligand sees reduced affinity of the other EGFR monomer binding site
Symmetric sees strong dimer and signalling.
Asymmetric sees partial agonism, different signalling characteristics and even biased signalling.
EREG and epigen seen to induce weaker dimers than EGF, however sees more sustained signalling - with bias towards cell differentiation as opposed to proliferation.
