1. CK402 Biochemistry
Answers:
1. Describe a growth factor signalling pathway highlighting components which are known
to contribute to the development of cancer.
A Growth factor signalling is a cell signalling pathway that regulates the growth and
development of an organism. Secreted growth factors are protein that bind to
transmembrane growth factor receptors to stimulate cell signalling cascades that promote
cell proliferation, division, apoptosis and differentiation. Activating mutations in growth
factor receptors or their signalling pathways commonly are associated with cancers.
There are many growth factor signalling pathways like TGF-β, EGF, FGF, MAP kinase
pathway, STAT pathway, Phosphatidylinositol 3-kinase/Akt Signalling Cascade etc.
RAS-RAF-MEK-ERK MAP Kinase Pathway
The epidermal growth factor receptor (EGFR) is a type of transmembrane receptor tyrosine
kinase (RTK) that couple the binding of intracellular signalling pathways to the extracellular
growth factor ligands and those pathways control various biologic responses such as
differentiation, proliferation, survival and cell motility. EGFR signalling pathway activated
by binding of receptor specific ligand which leads to the formation of a functionally active
EGFR-EGFR dimer or hetro dimer. It causes the ATP-dependent phosphorylation of specific
tyrosine residues in the EGFR intracellular(cytoplasm) domain.
The activated EGFR’s residues bind(attach itsely) directly to the GRB2(growth factor
receptor binding protein 2). GRB2 binds to the proline rich carboxy-terminal tail in SOS
(son of sevenless). SOS is a guanine nucleotide exchange factor (GEF). It activates RAS which
is a monomeric G-protein. RAS typically relies on guanine nucleotide-exchange factors
(GEFs) for binding GTP, and on GTPase-activating proteins (GAPs) for stimulation of GTP
hydrolysis. RAS once activated can dissociate and move in membrane to interact with other
kinases such as RAF.RAF gets activated upon interaction of RAS. RAF directly activates MEK
by phosphorylation. MEK (mitogen-activated protein kinase kinase-MAPKK) are a rare class
of tyrosine and threonine/serine dual-specificity kinases that activate ERK. MEK
phosphorylates the Thr-Glu-Tyr motif in the ERK.ERK is another kinase which then
2. translocate into nucleus and interacts with several transcription factors(TFs) and RNA
polymerase for an allow to gene expression to happen and this is how the downstream
cascade in RAS MAP kinase pathway takes place.
The genes that are transcribed by this pathway are responsible for growth and cell division
such as CYCLIN D1, and also genes which are responsible for survival, proliferation like
cMYC, BCL2, BCLxL etc. All of these genes are target genes for MAP kinase pathway. This
pathway gives rise to growth, division, proliferation in terms of tissue or cell.so it’s very
important for growing tissue or cell division. But mutations in the EGFR gene or any other
component of this pathway can lead to cancer.
Components contributing to the development of cancer
EGFR
Overexpression Of EGFR
Overexpression of receptor leads to increased activation of RAS-RAF-MEK-ERK pathway
because if there is more receptor it can bind to more ligand and cause the pathway to
become more activated. EGFR is amplified or mutated in a variety of cancers including in
highly lethal brain cancer glioblastoma (GBM), lung cancer, pancreatic cancer etc.
RAS
Mutation In RAS Oncogene
In the mutated RAS the GTP activated protein(GAP) cannot hydrolyse the GTP as a result
RAS is constitutively active regardless the presence of any ligand/mitogen. As a result,
downstream effectors such as RAF, MEK, ERK all are active and the genes are transcribed
which leads to uncontrolled proliferation which may leads to cancer.
Mainly pancreatic cancer is caused due to mutation in RAS protein. Thyroid and lung cancer
also occur due to RAS mutation.
RAF
There are three RAF protein (A, B, C). A point mutation occurs in B-Raf which leads to
constitutively active form of B-Raf. Melanoma, colon and thyroid cancer occur due to
mutation in RAF.
References:
Adrián Riesco, Beatriz Santos-Buitrago, Javier De Las Rivas, Merrill Knapp, Gustavo Santos-
García, Carolyn Talcott, "Epidermal Growth Factor Signalling towards Proliferation:
Modeling and Logic Inference Using Forward and Backward Search", BioMed Research
3. International, vol. 2017, Article ID 1809513, 11 pages, 2017.
https://doi.org/10.1155/2017/1809513
Capuani, F., Conte, A., Argenzio, E., Marchetti, L., Priami, C., Polo, S., ... & Ciliberto, A. (2015).
Quantitative analysis reveals how EGFR activation and downregulation are coupled in
normal but not in cancer cells. Nature communications, 6(1), 1-14.
Liu, F., & Mischel, P. S. (2018). Targeting epidermal growth factor receptor co?dependent
signalling pathways in glioblastoma. Wiley Interdisciplinary Reviews: Systems Biology and
Medicine, 10(1), e1398.
G. Vukmirovic and S. M. Tilghman, “Exploring genome space,” Nature, vol. 405, no. 6788, pp.
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Sever, R., & Brugge, J. S. (2015). Signal transduction in cancer. Cold Spring Harbor
perspectives in medicine, 5(4), a006098. https://doi.org/10.1101/cshperspect.a006098
