Human epidermal growth factor (hEGF) is a key molecule found extensively in various tissues and bodily fluids. Its ability to activate downstream signaling pathways through binding with EGFR makes it integral in physiological and pathological processes.
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Introduction of hEGF
Epidermal growth factor (EGF) was originally discovered in rodents and named for its direct promotion of epidermal growth and keratinization. Human EGF (hEGF) is derived from the hydrolysis of its precursor, with the gene located on the human chromosome 4q25-q27, consisting of 24 exons homologous to low-density lipoprotein receptor genes and transforming growth factor-alpha precursor genes. The hEGF precursor protein is a type I transmembrane glycoprotein composed of 1,207 amino acids, with multiple glycosylation sites. In the synthesis process, the insoluble hEGF precursor is initially anchored to the cell membrane and then released as mature hEGF through the cleavage by membrane-associated proteases.
Fig. 1 The two independent hEGF molecules A (inred) and B (in green) (Lu H. S., et al. 2001).
Mature hEGF, encoded by exons 20 and 21, has a molecular weight of approximately 6.2 kDa and an isoelectric point (pI) of 4.6. Its amino acid sequence includes six cysteine residues forming three pairs of intramolecular disulfide bonds, constituting the active center. Additionally, A, B, and C loops are formed intramolecularly, considered the most stable regions in the hEGF structure. Structurally, hEGF consists of a double-layered anti-parallel β-sheet connected by a β-turn and two α-helices, one at the N-terminus and the other at the C-terminus. The C-terminal domain is crucial for the binding of hEGF to its receptor, with Leu47 being a key amino acid residue. Experimental evidence indicates that the disruption of the C-terminal hydrophobic core and the exposure of Leu47 are critical steps in the binding of hEGF to the receptor and the initiation of signal transduction.
The Mechanism of Action of hEGF and Its Biological Effects
hEGF exerts its biological functions by binding to its receptor, EGFR (epidermal growth factor receptor). The EGFR gene encodes a 170 kDa type I transmembrane glycoprotein and belongs to the EGFR family, which includes EGFR, ErbB2, ErbB3, and ErbB4. The structure of the EGFR receptor comprises extracellular, transmembrane, and intracellular regions, with the extracellular region being rich in cysteine residues. hEGF can bind to EGFR through various mechanisms, including autocrine, juxtacrine, endocrine, and paracrine.
Upon binding, hEGF initiates the assembly of EGFR dimers, triggering the activation of the receptor tyrosine kinase (RTK) and resulting in the phosphorylation of tyrosine residues within the C-terminal domain of EGFR. The phosphorylated tyrosine residues serve as secondary messenger molecules, recruiting signal molecules equipped with SH2 (Src homology 2) and PTB (phosphotyrosine binding) domains. This recruitment process facilitates the transduction of extracellular signals into the cell. Subsequent to activation, various downstream signaling pathways, such as Ras/Raf/MEK/MAPK, JAK/STAT, PI3K/AKT, and PLCγ/PKC, come into play, exerting influence on cell proliferation, differentiation, and survival.
hEGF exhibits widespread distribution in various tissues and bodily fluids, including blood, milk, gastric fluid, and amniotic fluid, where it plays a regulatory role in diverse physiological and pathological processes. Its biological impacts encompass the promotion of cell division, synthesis of DNA/RNA/proteins, tissue proliferation, and differentiation. Furthermore, hEGF influences organ development, fosters interstitial cell proliferation, and holds therapeutic promise in corneal-related diseases. Beyond these effects, hEGF stimulates the production of cell factors and collagenases, facilitating wound repair, and inhibits gastric acid secretion, thereby protecting the gastric mucosa. It also influences stem cell dedifferentiation and enhances substance transport and glucose metabolism. These findings underscore the multifaceted regulatory functions of hEGF in cellular biology and physiology, offering potential therapeutic avenues for treating diseases and promoting tissue repair.
Applications of hEGF
The application research of hEGF reveals its widespread presence in various tissues and body fluids, activating downstream signaling pathways upon binding to EGFR and participating in various physiological and pathological regulatory processes. With strong cell proliferation and differentiation activity, hEGF stimulates the production of intracellular cytokines, synergizing with them to facilitate tissue regeneration and repair, particularly in the fields of gastric ulcers and wound healing, gaining attention with the rise of biomaterial research. However, considering its effects on promoting cell survival and inhibiting apoptosis, the impact of hEGF in the pathological processes of tumors cannot be ignored.
hEGF and Gastric Ulcers
hEGF, known for promoting the proliferation and differentiation of gastrointestinal mucosal epithelial cells, accelerates gastric mucosal regeneration. It also inhibits gastric acid secretion and increases mucosal blood flow, improving gastric ulcer treatment. Research suggests that hEGF, when delivered effectively, can enhance the healing of gastric ulcers. However, concerns about abnormal epithelial cell proliferation and potential tumor promotion have led to limitations in hEGF application. Innovative approaches, such as using recombinant hEGF probiotics, aim to target specific sites, showing promise in treating gastrointestinal ulcers without exacerbating related colorectal cancer.
hEGF and Wound Healing
hEGF, through autocrine and paracrine pathways, activates signaling pathways like MAPK and AKT, promoting cell proliferation and survival. It plays a significant role in wound healing by enhancing the synthesis of endogenous growth factors and collagenases. Studies on hEGF's effectiveness in treating diabetic ulcers and surgical wound repair have demonstrated positive outcomes. Various formulations and delivery systems, including liposomes and nanofiber scaffolds, aim to improve hEGF's bioavailability for enhanced wound healing.
hEGF and Cancer
While hEGF promotes cell proliferation, it also plays a crucial role in tumor development. Its interaction with EGFR activates downstream signaling molecules, facilitating tumor cell survival, growth, and metastasis. Targeting EGFR has become a focal point in cancer therapy. Despite its negative role in tumor pathology, the presence of hEGF holds significance in cancer diagnosis, prognosis, and treatment evaluation. Ongoing research explores the use of hEGF in cancer treatment, combining it with other agents to overcome resistance.
References
- Lu H. S.; et al. Crystal structure of human epidermal growth factor and its dimerization. Journal of Biological Chemistry. 2001, 276(37): 34913-34917.
- Shin S. H.; et al. The use of epidermal growth factor in dermatological practice. International Wound Journal. 2023, 20(6): 2414-2423.
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