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Epidermal Growth Factor Receptor (EGFR)

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Brendan Vonick

on 30 November 2012

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Transcript of Epidermal Growth Factor Receptor (EGFR)

Epidermal Growth Factor Receptor Brendan Vonick
Adam Siwek History Stanley Cohen, a professor at Vanderbilt University School of Medicine, discovered Epidermal Growth Factor (EGF) through his experiments with Nerve Growth Factor (NGF) and mice.
He injected the mice with salivary gland extracts containing NGF and found that they're eyelids opened earlier and their teeth grew sooner.
His suspicions lead to the discovery of a new factor that stimulated growth in cells of the epidermis. Consequently, he named this new factor 'Epidermal Growth Factor.' Shortly after identifying the amino acid sequence, he was able to determine the protein on the cell's surface that acts as it's receptor.
The receptor binds to EGF, and the EGF-receptor complex is taken into the cell.
This opened the door to vast new world in understanding growth factors and their receptors. Background Human EGF is a single-chain polypeptide consisting of 53 amino acid residues, including six Cys residues that form three disulfide bonds. The human EGF receptor (EGFR) is a 1186 amino acid transmembrane glycoprotein.
EGFR is a Receptor Tyrosine Kinase (RTK) belonging to the ErbB growth receptor family.
It is comprised of four members (Domains I-IV):
EGFR (also called ErbB1 or Human Epidermal Growth Factor Receptor -HER1)
ErbB2 (HER2)
ErbB3 (HER3)
ErbB4 (HER4) These Receptor Tyrosine Kinases are all structurally related in the sense that they transfer high-energy donor molecules (such as ATP) to specific target molecules (substrates).
EGFR signaling yields very important cellular responses and therefore must be regulated and controlled constantly. Several proteins that regulate EGFR signaling include CBL, CSK, PKC and PTEN.
Altering the signaling can have extreme consequences in humans ranging from Alzheimer's Disease to tumors and several cancers. Structure The first receptor tyrosine kinase (RTK) to be discovered was the EGFR.
Later, it yielded insight into the underlying mechanisms by which RTK functions, including the recruitment and activation of second messengers.
Structurally, ErbB family receptors present an extracellular ligand binding domain, a transmembrane domain that makes a single pass through the plasma membrane, and a cytoplasmic domain which harbors the intrinsic tyrosine kinase (TK) activity. In the ErbB family, this last extracellular ligand-binding domain exhibits four subdomains (or, more simply, I, II, III and IV respectively)
L1- Domain I
S1 (CR1) - Domain II
L2 - Domain III
S2 (CR2) - Domain IV
Of these domains, S1 and S2 are homologous, cysteine-rich regions (CR1 and CR2), while L1 and L2 form the ligand-binding site.
Cysteine residues do not form disulphide bonds between the two S1/S2 domains. The intracellular tyrosine kinase domain of EGFR is highly conserved while on the other hand, the extracellular EGFRs are able to bind to different ligands and are therefore much less conserved.
The EGFR ligand family includes over 10 molecules.
Specific binding legions to EGFR:
Activated by EGF, TGF-α, and several other ligands. Ligand Binding:
Induces or stabilizes receptor homo / heterodimerization with other EGFRs.
Tyrosine Kinases are activated, and phosphorylation of the dimerization partner occurs.
Brings the two cytoplasmic tyrosine kinase domains of the receptors close enough for autophosphorylation and to thereby activate the intrinsic tyrosine kinase activity.
Newly phosphorylated tyrosine residues are docking sites for intracellular signaling molecules.
Induce different downstream signaling pathways dependent of receptor pair combinations. Crystals of EGFR together with TGFα or EGF provided the first glimpse at the ErbBs’ extracellular domain.
EGFR dimer of 2:2 stoichiometry reveals that the ligands are located on opposite sides of the dimer.
Sharp contrast to other ligand: RTK complexes. Most striking feature of the ligand EGFR structures is an ordered β-hairpin loop.
Projecting away from the ligand binding site, which mediates receptor-receptor interactions, and is thus referred to as the ‘dimerization loop.’
Prior to ligand binding, the dimerization loop imposes an intramolecular ‘tethered’ conformation by bridging domains II and IV.
Preventing the formation of a high affinity ligand-binding site comprised of domains I and III. Dimerization Loop (Cont.) Upon ligand binding, a major conformational change detaches the intra-molecular tether and stabilizes the ‘active’ form, in which the unmasked β-hairpin loop projects outwards to mediate dimerization.
Ligand-less molecule is ‘locked’ in the active conformation, with the dimerization loop. constantly projecting outwards, and thus ErbB-2 is poised to interact with other family members. Dimerization Loop Works cited Bazley, L. A., and W. J. Gullick. "The Epidermal Growth Factor Receptor Family." Endocrine-Related Cancer. N.p., n.d. Web. 28 Nov. 2012.

Bublil, Erez, and Yosef Yarden. "ScienceDirect.com - Current Opinion in Cell Biology - The EGF receptor family: spearheading a merger of signaling and therapeutics." ScienceDirect.com | Search through over 10 million science, health, medical journal full text articles and books.. N.p., n.d. Web. 28 Nov. 2012.

"Cell - Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains." ScienceDirect.com | Search through over 10 million science, health, medical journal full text articles and books.. N.p., n.d. Web. 28 Nov. 2012.

EGFR, potentially targeting both, and p185. "ErbB receptors: from oncogenes to targeted cancer therapies." National Center for Biotechnology Information. N.p., n.d. Web. 28 Nov. 2012.

Garfield, Eugene. "Current Coments." Essays of an Information Scientist. N.p., 27 Apr. 1987. Web. 26 Nov. 2012.

"Nature Clinical Practice Oncology | EGFR inhibitors: what have we learned from the treatment of lung cancer? | Article." Nature Publishing Group : science journals, jobs, and information. N.p., n.d. Web. 28 Nov. 2012.

"Signaling Pathways: Inhibition of Apoptosis." Cell Signaling Technology. N.p., n.d. Web. 28 Nov. 2012.

Structure of the Extracellular Region of HER3 Reveals an Interdomain TetherHyun-Soo Cho and Daniel J. LeahyScience 23 August 2002: 297 (5585), 1330-1333.Published online 1 August 2002 [DOI:10.1126/science.1074611]

Wolfgang, Lilleby. "Radiotherapy and inhibition of the EGF family as treatment strategies for prostate cancer: combining theragnostics with theragates." Springer Images. N.p., n.d. Web. 28 Nov. 2012. EGFR Function The EGFR receptor pair combination induces several different signaling pathways. The four main ones include:
Ras-Raf-mitogen-activated protein kinase (MAPK) cascade
phosphoinositide 3-kinase (PI3K)-Akt cascade
Janus kinase (JAK) and the signal transducer and activator of transcription (STAT) cascade
protein kinase C (PKC) cascade The MAPK pathway communicates a signal from the EGFR on the surface of the cell to the DNA in the cell’s nucleus.
After the EFG-EFGR complex enters the cell, Ras (a GTPase) is phosphorylated and activates RAF (MAP3K). This in turn activates MAP2K and then MAPK which ultimately activates a transcription factor. MAPK Cascade PI3-Akt Cascade The PI3K pathway leads to the activation of Akt, an important player in survival signaling.
Akt regulates cell growth by affecting mTOR and p70 S6 kinase pathways.
It regulates the cell cycle and cell proliferation through its direct action on some CDK inhibitors and the levels of some cyclin.
Akt also mediates cell survival through direct inhibition of pro-apoptotic signals such as Bad and the Forkhead family of transcription factors. STAT Cascade This signaling event phosphorylates the tyrosine of the STAT protein, activating it. EGFR can activate STAT by first activating JAK, or by bypassing this process and directly acting upon STAT.
STAT proteins bind to another through dimerization and translocate to the nucleus where they activate transcription of the target genes. Protein Kinase C Cascade EGFR activates several forms of PLC (phospholipase C), including the G1 isoform.
This enzyme catalyzes the hydrolysis of PIP2 generating the second messengers of DAG and IP3. IP3 releases stored Calcium ions from the ER and DAG activates PKC.
PKC has a wide array of cellular uses including augmenting the MEK1 and MEK2 transcription cascades, the activation of IKKs and nuclear factor NF-KappaB-dependent transcription. Insufficient ErbB signaling Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease. Neurons need a constant supply of growth factors for their survival, and withdrawal of these factors or blocking their signal pathways leads to cell death.
Excessive EGFR signaling also triggers cell death, and increasing EGFR activity is extremely dangerous to cell survival.
Two plausible methods of preventing neuronal cell death in neurodegenerative diseases include increasing EGFR activity only a small, moderated amount. Perhaps finding supplemental growth factors and bypassing EGFR signaling is a way in which neurons can attain sufficient growth factors without initiating apoptosis (the 'self-destruct button' in a cell). Excessive ErbB signaling, on the otherhand is associated with the development of a wide variety of types of tumors and cancers.
Multiple evidences indicate that elevated EGFR expression is an important determinant of radiation response and that EGFR exhibits a radioprotective function for cancerous cells, preventing apoptosis. Excessive ErbB signaling The radiation resistance occurs because of activation of signaling cascades leading to tumor cell survival, repopulation, and proliferation.
The radioprotective functions of EFGR are divided into three phases based on time. Phase 1: Early DNA Repair (0-4 h) This phase involves radiation-induced translocation of EGFR and interactions with the DNA repair enzyme, DNA-dependent protein kinase (DNA-pk’s)
Irradiated EGFR binds to catalytic regulatory subunits of DNA-pk, DNA-pkCS and the regulatory subunits Ku70 and Ku80 of DNA-pk.
This radiation induced DNA-pkCS phosphorylation controls the disassembly of DNA-pkCS and the rejoining of DNA double strand breaks (DSBs), resulting in cell survival. Phase 2: Inhibition of DNA Damaged Induced Apoptosis Phase(4–24 h) Normally, tumor cells undergo rapid apoptotic cell death prior to cell division. However, radiation-induced activation of EGFR confers resistance to apoptosis through activation of the PI3K and Akt signaling pathway causing the cell to survive. Phase 3: Proliferation and repopulation phase (>24 h) After the repair of DNA damage, EGFR-dependent Ras/Raf/MEK/ERK and STAT signaling pathways are activated leading to proliferation and repopulation advantage. This leads to the conclusion that EGFR inhibitors might lead to sensitizing tumors and therefore blocking these hazardous pathways.
Tumors are vascular and bind blood vessels to the EGFR causing activation and further spreading of the tumor. Inhibitors destroy tumor vasculature and prevent growth. Cancer can be thought of as a raging wildfire. It is a destructive force that is harmful to everything in its path.
The combination of EGFR inhibitors with radiotherapy is more effective in stunting cancer growth than irradiation alone. EGFR Inhibitors and Radiation Therapy Radiation combined with EGFR inhibitors in preclinical studies have been shown to lead to the “…direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization through modified signal transduction, inhibition of repair of DNA damage, reduced repopulation and improved reoxygenation during fractionated radiotherapy. Even today, little is known about EGFR’s effect on normal tissue.
In organ growth, EGFR plays a critical role in mediating morphogenesis and differentiation.
EGFR also plays a role in epithelial tissue renewal, such as that of the gastrointestinal tracts, as EGFR helps mediate cell proliferation.
Further studies are required to fully understand the functions of EGFR in organisms, but one thing is certain, it is a vital contributor to life as we know it. Modern Studies and Applications
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