Epidermal Growth Factor (EGF)
Epidermal growth factor (EGF) is a growth factor best known for its ability to stimulate cell growth and proliferation. EGF was discovered as a result of the initial observations of Stanley Cohen and coworkers in the 1950s (Cohen 1986) in which the injection of extracts from mouse salivary glands into newborn mice resulted in precocious eyelid opening and tooth eruption. Subsequent studies revealed more generalized biological effects of salivary gland extracts, including enhancement of epidermal growth and keratinization. The factor mediating these effects was identified as a 6-kDa peptide of 53 amino acids and was thus named the epidermal growth factor. In later years and independent of these studies, urogastrone, long known as inhibitor of gastric acid secretion, was isolated from urine and found to be the human form of mouse EGF. EGF has now been detected in various additional body fluids and tissues including milk, urine, plasma, intestinal fluid, amniotic fluid, kidney, brain, prostate fluids, duodenum, and placenta and has diverse cellular effects ranging from mitogenesis to the promotion of hormone secretion to glucose metabolism and cell differentiation (Carpenter and Cohen 1979). For the ground-breaking work on EGF, Stanley Cohen was awarded the 1986 Nobel Prize in Physiology and Medicine together with another pioneer in growth factor biology, Rita Levi-Montalcini, who discovered the functionally distinct nerve growth factor (NGF).
EGF Family of Proteins
EGF Receptors (EGFR)
EGFR/HER1 (Dreux et al. 2006; Lemmon et al. 2014) is the primary receptor for EGF and is encoded by a gene located on the short arm of chromosome 7 (p11.2). The mature 170 kDa type 1 transmembrane protein consists of 1186 amino acid residues with a 621 amino acid highly N-glycosylated extracellular domain, a 23 amino acid transmembrane region, and a 542 amino acid cytoplasmic domain. Within this domain, the juxtamembrane region that is conserved between EGFR family members is involved in receptor downregulation, ligand-dependent internalization, and basolateral sorting. The EGFR ectodomain has four subdomains (I-IV) composed of two sets of tandem repeats with domains I and III providing ligand specificity and domains II and IV being highly enriched in cysteine regions that form several disulfide bonds. Together they create the ligand-binding pocket which in the absence of ligand is locked into an autoinhibitory confirmation thereby preventing the exposure of the dimerization motifs. Binding of EGF to EGFR or that of other members of the EGF growth factor family to their respective receptors increases the affinity of the receptor to the growth factor and results in a conformational shift leading to homodimeric or heterodimeric interactions between the different receptors and activation of the intracellular tyrosine kinase domain (Lemmon et al. 2014). Dimerization is accompanied by autophosphorylation of tyrosine residues in the cytoplasmic tails of the receptors which serve as docking stations for adaptor and signaling molecules leading to activation of the EGFR/ErbB signaling cascades. Within the cytoplasmic domain, the phosphorylation of specific tyrosine residues is linked to the binding of discrete signaling molecules thereby leading to the activation of defined intracellular signaling pathways and for termination of receptor signaling through endocytosis and targeting to lysosomes for degradation.
EGF in Development, Tissue Regeneration, and Tumor Formation
Much of our understanding of the developmental, physiological, and pathological roles of EGF has come from transgenic mouse models (Zeng and Harris 2014). Mice with widespread expression of human EGF have low birth weight and stunted growth and abnormalities in chondrocyte and bone development with hyperproliferation of osteoblasts. Adult male mice are sterile, but surprisingly do not develop tumors. Mice with overexpression of mouse EGF have abnormalities in fur development and behavioral changes in addition to the phenotypic changes observed with human EGF. Studies in pre-implantation embryos suggest that EGF is an important mitogenic factor during early development acting synergistically with other growth factors. However, EGF knockout mice have no overt phenotype suggesting that EGF family members are functionally redundant and can compensate for loss of EGF function. This is in stark contrast to the effect of EGFR knockout in mice that, depending on the genetic background, varies from embryonic lethality to death at birth or postnatal death with defects in bone, brain, heart, skin, and lungs and various other epithelia.
In addition to its function in embryonic stem cells during development, EGF also plays important roles in stem or progenitor cells during wound healing and tissue renewal. EGF has been shown to be important for stem cell function in a variety of tissues, including brain, heart, bone marrow, intestine, and skin and can function synergistically with other growth factors to expand stem cell populations (Zeng and Harris 2014). In combination with LIF (leukemia inhibitory factor) or CNTF (ciliary neurotrophic factor), EGF can reprogram acinar cells into insulin-producing beta-like cells in diabetic mice. In wound healing, the response to EGF is diverse and may differ between acute and chronic wounds. EGF is upregulated after acute wounding to promote epithelialization and downregulated in chronic wounds.
Most of our knowledge on EGF signaling and cancer has come from studies on the family of EGFR/ErbB receptors. Abnormal receptor expression, oncogenic EGFR mutations, decreased internalization, and other trafficking defects that lead to altered or prolonged signaling all have been shown to play a role in tumor development and progression. The complexity of the interactions between ligands of the EGF family of growth factors with the EGFR/ErbB family of receptors that can form diverse combinations of homo- and heterodimers and the observation that EGF overexpressing mice do not develop tumors point to a multifaceted relationship between EGF signaling, EGFR, and cancer. Studies on a direct role of EGF in tumor development are more limited. However, increased expression of EGF has been correlated with aggressive tumor growth and metastasis. EGF can increase tumor cell proliferation and migration through MAPK and PI3K signaling, increased expression of MMPs (matrix metalloproteases), and by promoting EGFR localization to the nucleus to activate gene transcription (Edwin et al. 2006; Tebbutt et al. 2013) which is consistent with EGF promoting oncogenesis via the activation of EGFR.
Since its isolation by Cohen and coworkers, EGF has likely become the best known growth factor in biology. Studies on EGF function, the identification of additional members of the EGF growth factor family, and the characterization of their receptors and associated signaling cascades has aided tremendously in our understanding of fundamental physiological processes such as development and tissue regeneration. Along this path, it has become clear that dysregulation of EGF function is associated with the pathogenesis of various diseases ranging from renal hypomagnesemia to cancer development. Still, the biology and regulation of EGF is not as well understood as that of some of the other members of the EGF family of growth factors.There is also a wealth of knowledge of the biological and pathological functions of EGFR, but studies show that EGF and EGFR can have biologically distinct functions. These gaps in knowledge will still have to be closed in order to develop novel therapeutic strategies that directly target EGF with high specificity and efficacy.
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