2. Growth Factor & GFRs Flashcards
List a few type of cells that may be present in the tumour cell micro environment
- Fibroblasts
- Cancer cells
- Macrophages (TAM)
- Endothelial (blood vasculature)
- T cells (immune cells)
What are the 4 types of growth factors?
- Receptor tyrosine kinases (RTKs)
- Receptor Serine-Threonine kinases
- Trans-membrane domain receptors
- G protein coupled receptors
What types of GFs do NOT act by phosphorylation
Trans-membrane domain receptors & G-protein coupled receptors
What are 3 examples of receptor tyrosine kinases and their respective ligands?
ErbB/HER1 : EGF
Flt/KDR : VEGF
cMet : HGF
What are 2 examples of serine-threonine receptor kinases and their respective ligands?
Smad : TGF-b
ALK1-7 (Activin-like kinase) : BMP
What is the difference between ALK1-7 and ALK?
ALK1-7 : Activin-Like Receptor, it is a serine-threonine kinase
ALK: Anaplastic lymphoma kinase (a receptor tyrosine kinase)
What is an example of a G-coupled receptor and its ligand?
Frizzled : Wnt
What types of cancer/process are driven by the RTK-mediated growth factors:
- EGF
- VEGF-A
- VEGF-C
- HGF
- FGF1
- PDGFA/B
- EGF: breast & lung cancer
- VEGF-A: angiogenesis -> tumour growth
- VEGF-C: lymphangiogenesis -> metastasis
- HGF: liver metastasis
- FGF1: bile duct cancer
- PDGFA/B: sarcoma, GI stromal tumours (GIST)
What are the RTKs associated with these cancers/processes?
- breast & lung cancer
- sarcoma & GI stromal tumours
- angiogenesis
- bile duct cancer
- lymphangiogenesis
- breast & lung cancer: ErbB1-4 (EGFR, HER2-4)
- sarcoma & GI stromal tumours: PDGFRA/B
- angiogenesis: VEGFR2, KDR
- bile duct cancer: FGFR1
- lymphangiogenesis: Flt4
What is the GF and the GFR associated with acute myeloid leukemia?
GF: granulocyte colony stimulating factor (GCSF)
GFR: CD114
Fill in the blanks:
____, an EGFR used for NSCLC had an ____ in median survival in patients with stage IV cancer who had failed chemo
1) Erlotinib
2) increase
Describe the structure of a receptor tyrosine kinase
The extracellular domain is made up of leucine-rich repeats and cysteine domains.
The transmembrane domain (TMD) exists between the intra- and extracellular regions
The juxtamembrane connects the TMD to the tyrosine (symbol = Y) kinase domain.
Fill in the blanks:
Receptor Tyosine Kinases signal through _____ _____.
Phosphorylated ____ are recognised by ____ ____ domains in proteins.
Adaptor proteins like ____ have SH2 and SH3 domains.
SH3 domains recognise ____ rich regions in ____ proteins (____)
____-____ase converts GTP->GDP
____ causes Ras to release GDP
1) tyrosine phosphorylation
2) tyrosines
3) Src homology2 (SH2)
4) Grb2
5) proline
6) adaptor
7) Son of Sevenless (SOS)
8) Ras-GTP
9) SOS
Describe an overview of the EGFR signalling:
- Ligand (EGF) binds
- Induces conformational change in EGFR -> homo/hetero dimerisation.
- Monomer phosphorylates tyrosine residues on cytoplasmic tail of other monomer.
- TyrP docks adaptor proteins, including Grb2, SHC, which facilitate assembly of signalling complexes
- Recruitmentment of SOS activates Ras-GTPase -> MAPK pathway -> TF activation
- Activation of P13K/Akt pathway -> TF activation
- degradation of EGFR/ induction of inhibitors (PTEN) to regulate EGFR signalling.
Describe the function of Grb2 and its domains
- Grb2: Grabs phosphorylated tyrosine kinases and forms link
Domains: Src Homology (SH) 2&3 - SH2: binds to +PY
- SH3: binds to other proteins (eg SOS) that form signalling complex
How does the structure of Grb2’s domains result in an amplified signal?
The ratio of SH2 :SH3 is 1:2, meaning the SH3 can bind 2 adaptor proteins for every 1 phosphorylated tyrosine that SH2 binds
Describe the function of the SOS guanine exchange factor in EGFR signalling
SOS binds through proline rich domains to Grb2 to initiate signalling complex.
SOS recruits RasGTPase
converts GTP->GDP, initiates downstream signalling eg Ras > Raf (MAPK pathway)
What is the downstream transcription factor of the MAPK pathway
C-Myc
Outline the P13/Akt signalling pathway from EGFR
EGFR dimerisation
SHC adaptor proteins
Kinases: Src > P13K > AKT (> Cyclin D, indirect)
-> BAD (adaptor) & casp9 (protease) -> survival of cell
In what ways are the VEGFR and EGFR pathways:
- similar
- different
Similar:
- Activates MAPK and P13/AKT pathways
- Results in survival & prliferation of cell
Different:
- VEGFR activates PKC pathway
- EGFR = RTK, VEGFR = IgG
How can GF pathways be hijacked in cancer?
- Excess GFR expression
- Excess GF signalling
- Excess GF production
What regions of a gene may be mutated when GFs are over-expressed?
Enhancer or Promoter regions
Why does over-expression of GFs cause enhanced signalling?
GFRs work by dimerisation
Increase expression leads to ligand-index dent activation
(increase probability of dimerising & interacting regardless of ligand presence)
Drives GFR signalling
Why is HER2 a good target when EGFR signalling is over-expressed?
HER2 can homodimerise and heterodimerise (with EGFR4,3,1) drives expression, and means other GFRs do not need ligand
