Structural characteristics and signaling regulation mechanisms of chicken-derived epidermal growth factor protein

Growth factors are a class of polypeptides that regulate cell growth and various other biological functions by binding to specific, high-affinity receptors on the cell membrane. In academic literature, they are often referred to as "growth peptides." These molecules are widely distributed in various tissues of the body, including developing embryonic tissues and differentiated mature tissues. Growth factors primarily exert their regulatory effects through autocrine or paracrine pathways, playing indispensable roles in numerous physiological and pathological processes such as immune responses, hematopoietic regulation, tumorigenesis, inflammation and infection responses, wound healing, angiogenesis, cell differentiation and apoptosis, morphogenesis, and embryonic development.

The growth factor family comprises numerous members, each exhibiting significant specificity toward different cell types. Among them, epidermal growth factor (EGF) is one of the most extensively studied and widely applied classic molecules, and its discoverers were awarded the Nobel Prize in Physiology or Medicine.

Structurally, human epidermal growth factor consists of 53 amino acid residues, with a molecular weight of approximately 6.2 kDa and an isoelectric point of 4.6. It exhibits strong stability against heat, acid, and proteases. The conserved six cysteine residues in its amino acid sequence form three intramolecular disulfide bonds, creating three loop domains (A, B, and C), which constitute the active center of the EGF molecule. The human EGF gene is located on chromosome 4q25-q27, and the precursor is processed by proteolytic cleavage to release the mature peptide.

Human EGF initiates signal transduction by specifically recognizing and binding to the epidermal growth factor receptor (EGFR) on target cells. EGFR belongs to the ErbB receptor family and is a type I transmembrane glycoprotein with a molecular weight of approximately 170 kDa. Its extracellular domain serves as the ligand-binding region, while the intracellular domain possesses tyrosine kinase activity. Upon ligand binding, EGFR undergoes homodimerization or heterodimerization, leading to phosphorylation of specific tyrosine residues in the intracellular domain. This recruits signaling molecules containing SH2 or PTB domains, activating downstream signaling cascades such as Ras/Raf/MEK/ERK, PI3K/AKT, JAK/STAT, and PLCγ/PKC. This signaling network ultimately regulates the expression of genes related to cell proliferation, differentiation, and survival (e.g., myc, fos) at the transcriptional and translational levels, while enhancing DNA topoisomerase activity to drive cell cycle progression.

Chicken epidermal growth factor protein shares high structural and functional homology with human EGF but exhibits notable species-specific differences. Studies have shown that the cDNA sequence of the chicken EGFR is highly similar to that of human EGFR, encoding a glycoprotein of approximately 170 kDa. However, functional studies indicate that murine EGF has about 100-fold lower binding affinity for the chicken EGFR compared to the human receptor, suggesting species-specific differences in ligand-receptor recognition.

Notably, human transforming growth factor-alpha (TGF-α) binds to the chicken EGFR with affinity comparable to or even better than that of human EGFR. In mouse cells expressing chicken EGFR, TGF-α stimulates DNA synthesis about 100 times more efficiently than EGF. This phenomenon indicates that avian EGFRs exhibit distinct ligand recognition patterns compared to mammalian receptors, likely reflecting species-specific adaptations formed during the co-evolution of ligands and receptors.

Functionally, chicken EGF plays a critical role in embryonic development. Studies have confirmed that chicken embryonic lung tissue contains specific EGFRs that respond to EGF with mitogenic effects, and this response strengthens as embryonic development progresses. Additionally, endogenous EGF-like molecules are present in chicken embryonic tissues, suggesting that the EGF signaling system functions in an autocrine or paracrine manner during avian organogenesis.

Given the central role of the EGF signaling pathway in cell proliferation, tissue repair, and embryonic development, chicken EGF holds significant value in multiple research fields. In basic biology, it can be used to elucidate species-specific regulatory mechanisms of the EGF/EGFR pathway, serving as an important tool for comparative and evolutionary developmental biology. In agricultural biotechnology, chicken EGF can be applied to studies on poultry embryonic development regulation, intestinal mucosal repair, and growth performance optimization, with its role in regulating intestinal stem cell niches being particularly noteworthy.

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