Epidermal Growth Factor(EGF)

Presented By - Jayanta SahaMsc

Entry No-2015CHS1003

•Contents:Two important type of cell

Epidermal Growth Factor

EGF Pathway & Transduction Process

MAPK signaling pathway in tumor cell with RAS mutation

Treatment Technique

Epidermal Growth Factor• Two important type of cell is found in our

body-1.Epithelial cells are covers the all inner

organism2.Epidermal cells are found in skin

Epidermal Growth FactorNow What is Epidermal Growth Factor?EGF is simple protein molecule, that acts as a primary messenger that initiate the EGF signal transduction pathway.

Epidermal Growth Factor

• EGF Pathway:

• EGF receptor consists of two monomer which is identical but separated monomer unit. Each monomer contain

• 1. A binding site of EGF on the extracellular matrix

• 2.A tyrosine kinase on the intracellular side

• When the EGF molecule binds with extracellular EGF receptor ,they induced the dimerization .

• During the conformational change on extracellular receptor the tyrosine kinase also changes its conformation & the carboxyl moiety moves into active site of TK (tyrosine kinase ) which phosphorylates the c tail this is called crossed phosphorylation

• It create the attachment point of other proteins.

• EGF TRANSDUCTION PROCESS:

• Erk1&2 activates the many promoter region of DNA

.

Some important Protein factors:

GRB-2 -growth factor receptor bounding protein ,its have a anchoring effect for bound SOS protein.

SOS- Son of Sevenless (SOS) refers to a set of genes encoding guanine nucleotide exchange factors that act on the Rassubfamily of small GTPases.

RAF-Raf kinases are a family of three serine/threonine-specific protein kinasesthat are related to retroviral oncogenes

ERK-Extracellular signal regulated kinase ,It stimulate transcription factor

.• Function Of EGFR:

1. Cell growth

2. Cell Proliferation

3. Angiogenesis

4. Signaling many Protein Synthesis, like Cyclins, CDKs

•Another Way to think about Cancer?

• Cancer is a dieses of An aberrant signaling processing

• Oncoproteins & Tumor suppressors create cancer through their ability to generate signaling imbalance.

• RAS mutation• All Ras protein family members belong to a class of protein called small GTPase, and are

involved in transmitting signals within cells.

• It is 'switched on' by incoming signals, it subsequently switches on other proteins like Ref, Mek, Erk etc. ,which ultimately turn on genes involved in cell growth, differentiation and survival. As a result, mutations in ras genes can lead to the production of permanently activated Ras proteins. This can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals. Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer.

• The 3 Ras genes in humans (H-ras, K-ras, and N-ras) are the most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20% to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer).

•Treatment Technique :oRGD-Based Strategies To Target Alpha(v)

Beta(3) Integrin:(Fabienne Danhier, Aude Le Breton, and Veronique Pre ́ t , RGD-Based

Strategies To Target Alpha(v) Beta(3) Integrin in Cancer Therapy and Diagnosis, Molecularpharmaceutics)

The RGD sequence (Arg-Gly-Asp) was first discovered in the early 1970s by E. Ruoslahti as a cell attachment site in fibronectin. Later, this sequence has been recognized as the minimal integrin sequence present in many natural ligtnds binding αvβ3 receptor.

• RGD-Based Strategies To Target Alpha(v) Beta(3) Integrin:(

• (A) RGD antagonists.

• (B) RGD conjugates. The RGD-based peptide or peptidomimetic is conjugated to drugs or radionuclides with covalent links.

• (C) RGD peptides orpeptidomimetics are grafted at the nanoparticle surface (polymeric nanoparticles, liposomes, polymeric micelles, etc.). These structurescontains various agents such as anticancer drugs, peptides or proteins,nucleic acids, radionuclides, contrast agents, or a mixture of contrastagents and anticancer drugs.

Chemical structures.

(A) The original RGD sequence.

(B) Cyclic RGD peptide antagonist (c(RGDf[N-Me]V) or cilengitide.

(C) Cyclic peptide c(RGDfK).

(D) ACDCRGDCFCG (RGD4C).

(E) Example of RGD peptidomimetic-containing the RGD sequence (S-247).28

(F)Example of RGD peptidomimetic

• .Roles of he αvβ3 in egrin in angiogenesis:

•

• Angiogenesis Process:

• Vasodilation & increased vascular permeability mediated by VGEF

• Separation of Pericytes

• Basement membrane degraded by Matrix Metalloproteinase

• Migration of endothelial cell

• Proliferation of endothelial cell

• Remodeling into capillary tubes.

• Angiogenesis Process:

•Treatment Technique : Chemical conjugate of low molecular weight heparin and suramin fragment

inhibits tumor growth possibly by blocking VEGF: (Jooho Park, Ji-young Kim, Seung Rim Hwang, FoyezMahmud, and Youngro Byun .Mol. Pharmaceutics)

Angiogenesis is a fundamental process for tumor growth

Among angiogenic growth factors, vascular endothelial growth factor (VEGF) plays a key role

One of the unique characteristics of VEGF is that it contains a heparin-binding domain (HBD)

• Chemical conjugate of low molecular weight heparin and suraminfragment inhibits tumor growth possibly by blocking VEGF:

• Several studies have shown the inhibitory effects of heparin and heparin derivatives on tumor angiogenesis through their targeting of angiogenic growth factors. However, clinical applications of LMWH for anticancer therapy have been restricted due to its anticoagulant effect and insufficient therapeutic efficacy.

• To overcome these limitations and enhance the antiangiogenic efficacy, LMWH was conjugated with suramin fragments that have a binding affinity to the heparin-binding domain (HBD) of proteins

• Now What is Heparin & Suramin?

• Heparin: Heparin is a naturally occurring polysaccharide that inhibit the coagulation. Low Molecular Weight (LMWH) in contrast consist of only short chain of only saccharide.

• Suramin: suramin , developed by Bayer, is a hydrophilic polysulfonatednaphthylurea. Suramin inhibits the activities of various growth factors including human fibroblast growth factor (hFGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and transforming growth factor-beta (TGF-β), hus i is considered o possess po en tn i umor tc ivi y

• Schematic synthesis protocol and molecular structures showing low molecular weight heparin-suraminfragment conjugate(LHsura).

• Other inhibiter of EGFR:

• Cetuximab• Geftinib• Erlotinib• Afatinib