Structural Biochemistry/Cell Signaling Pathways/Epidermal Growth Factor Signaling

Epidermal Growth Factor Signaling

An epidermal growth factor or EGF is a type of growth factor that controls the proliferation, differentiation and survival of a cell. It is found in all living organisms. The purpose of EGFs is to protect all living tissue by sending out signals for other cells to multiply or release certain chemicals. EGFs are secreted by cells and released into the external environment where they may bind to epidermal growth factor receptors or EGFRs. Upon binding, the EGFs can dimerize with themselves (homodimer) or dimerize with other growth factors (heterodimer). Once dimerized, the inner side of the EGFR that contains a protein kinase adds a phosphoryl group (donated from ATP) to tyrosines on neighboring chains. In doing so, proteins attach to the newly phosphorylated tyrosines thus activating a signaling cascade that ends with DNA synthesis and cell growth.

File:Modular struture.jpg

The modular structure of the EGF receptor: the amino acid position of the EGF receptor proves that he EGF-binding site is outside the cell, one transmembrane helix domain, one intracellular tyrosine kinase domain, and the one tyrosine-rich site at the last carboxyl group.

The EGF signaling is stopped by protein phosphatases and the actions of Ras (GTPase activity). Important phosphatases kick off the phosphyl groups from the tyrosine residues on the EGF receptor and from the serine, threonine, and tyrosine component on the protein kinases that are involved in the signaling mechanism. The activation of the phosphatases is the result of the whole signaling process. Therefore, the signal activation must start the signal termination as well.

**Examples of Ras Superfamily of GTPases**
Subfamily	Function
Ras	Regulates cell grown via the serine-threonine kinases
Rho	Reorganizes the cytoskeleton via the serine-threonine kinases
Arf	Activates the ADP-ribosyltransferase of cholera toxin A subunit, regulates vesicular pathway, activates phospolipase D
Rab	Helps the secretory and endocytotic pathways
Ran	Operates in the transport of RNA and protein into and out of the nucleus

History

Epidermal Growth Factors and Receptors were found by Nobel Prize winner Stanley Cohen. While at Washington University in the 1950s, Cohen had been researching nerve growth factors in mice when he discovered EGFs. Research since then has shown promise for anti-cancer drugs and with cosmetics.

Structure

EGF structure is critical to cell response. EGFs cause the replication of targeted cells and thus need a specific structure to ensure that non-targeted cells are targeted. Note that cancer cells are capable of self-replication without the use of EGFs.

The most important structure in EGFs are disulfide bonds that result from long chains of cysteine residues. These disulfide bonds make it possible for the differentiation between the many types of EGFs.

Computer generated picture of an EGF

Types of EGF Proteins

Epidermal growth factors is a class of EGF proteins. All of these proteins are extremely similar in structure, composition, and function.

Heparin-binding EGF-like growth factor (HB-EGF)-plays a role in wound healing, cardiac hypertrophy, and heart development.
Transforming growth factor-α (TGF-α)-promotes neural cell proliferation.
Amphiregulin (AR-promotes growth of the normal epithelial cells and it inhibits growth of aggressive carcinoma cell lines.
Epiregulin (EPR)
Epigen
Betacellulin (BTC)
Neuregulin-1 (NRG1)-development of the nervous system and the heart.
Neuregulin-2 (NRG2-induces growth and differentiation of epithelial, neuronal, glial, and other cell types.
Neuregulin-3 (NRG3)-stimulates tyrosine phosphorylation on the receptor tyrosine kinase ErbB4.
Neuregulin-4 (NRG4).

General form:

CX₇CX₄-5CX₁₀-13CXCX₈GXRC

X represents an amino acid