The document discusses the role of normal and altered epidermal growth factor receptor (EGFR). EGFR is a tyrosine kinase receptor that binds EGF as a ligand and signals cell growth and division. Alterations in EGFR, such as mutations or deletions of the extracellular domain, can cause the receptor to signal independently of ligand binding and promote oncogenesis. Cancers commonly exhibit overexpression or amplification of EGFR. Knocking down altered EGFR using techniques like CRISPR could help study its effects on cancer cell signaling pathways like Ras.

1. Role of Normal and
Altered EGFR
PRESENTED BY
EDREES KHAN RAHMATZADA

2. Introduction
 EGF was initially characterized because of its ability to provoke premature
eye opening in newborn mice and later it is applied as a mitogenic effects
in many epithelial cell type.
 EGF functions as a ligand for EGFR.
 EGF and its family of receptors (ErbB1 or Her1) is a tyrosine kinase receptor
was first discovered and more ErbB2 (Her2), ErbB3 (Her3), ErbB4 (Her4)
identified other member of family.

3. Function of EGFR
 Getting the signals from the growth factor outside the cells to inside the
cells and to nucleus, where gene expression is regulated, passed through
different steps: binding of GFs to the receptors, receptor dimerization,
autophosphorylation, and activation of interacellular transducer like Ras.

4.  Isolation of receptors from the normal cell is really difficult. First is was
isolated from human uterus carcinoma cell line and showed elevated level
of EGFR about 10 fold more than normal cells.
 Its N-terminal domain with 621 amino acid residues, protrudes into
extracellular domain and recognize and bind with EGF ligand, and extend it
to the plasma membrane with 23 amino acid residue which is hydrophobic
in nature and C- terminal domain extend to the cytoplasm with 542 amino
acids.
 GFs binds with ectodomain of EGFR and a signal is transmitted through the
plasma membrane to activate the cytoplasmic domain of the receptors and
induces a cell to grow and divide.
 Dimerization brings two monomers of EGFR together to form dimer, it
happens due to the change in confirmation of single receptor; EGFR can
form heterodimer with other member of ErbB2.

5.  After the dimerization of the receptor enables kinase domain of one receptor
of the dimer to phosphorylate the other receptor at their tyrosine residues.
 Activation of tyrosine kinase domain facilitate additional phosphorylation of
tyrosine kinase which create high affinity binding sites for the proteins that
contain Src homology 2(SH2) domains and act as a docking site for the
recruitment of specific intercellular proteins.
 SRC, ABl, Grb2 and PI3-K are Sh2 domain containing proteins, out of them
 Grb2 contain both of the SH2 and Sh3 domain, SH2 domain recognizes
phosphorylation of EGF receptor and interact with SOS, which activate
oncogenic Ras proteins which transducer signals from membrane to the
cytoplasm in response to growth factor stimulation.

6. How does a growth factor receptor
behave as a oncoproteins
 EGF receptor is closely related to the sequence of known oncoprotein
erbB.
 erbB oncogene of avian erythroblastosis virus was found lack of
ectodomain. Without this domain receptor could not bind to the GFs in
normal cell lines.
 Mutation in receptors or deletion of ecotodomain, encoding for the GFs,
truncated receptors start to ligand independent firing of receptors.
 As shown in figure , mutation in the transmembrane (red spot) or
truncated ectodomain (deleted ectodomain) causes receptor independent
signal transduction and deregulation of signaling.

8.  So cancer cells are less independent to the growth factors for their growth
and survival. Truncated forms of EGF receptors are found in many human
tumor cell types.
 Mutations that lead to EGFR overexpression (known as upregulation or
amplification) have been associated with a number of cancers,
including adenocarcinoma of the lung (40% of cases), anal
cancers,[16] glioblastoma (50%) and epithelian tumors of the head and
neck (80-100%).

9. Conclusion
 EGFR is the main activator of the Ras oncogenic pathway in a cell.
 Which leads to cell survival and inhibition of cell apoptosis
 We can further do a research and knock down the EGFR with CRISPR/case9
or siRNA and knockdown the EGFR and screen them and can show the
effects of it in a cell.
 Especially with help of western blot we can show the Ras pathway proteins
whether in case of knock downing the EGFR whether the Ras oncogenic
pathway is active or not.
 And with help of PCR we can show the gene expressionof different
oncogenic pathway especially Ras pathway.

10. Thank You

11. References
 Weinberg, R. A. (2014). The Biology of Cancer. New York, NY: Garland
Science.
 “Epidermal Growth Factor Receptor.” In Wikipedia, September 23, 2019.
https://en.wikipedia.org/w/index.php?title=Epidermal_growth_factor_recep
tor&oldid=917395056.
 “Emerging Functions of the EGFR in Cancer.” Accessed October 4, 2019.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748484/.