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Epidermal growth factor

Epidermal growth factor (EGF) is a small mitogenic polypeptide consisting of 53 amino acids that promotes cell proliferation, differentiation, and survival, particularly in epithelial tissues, by binding with high affinity to its specific receptor, the epidermal growth factor receptor (EGFR). Discovered in the early 1960s by Stanley Cohen during studies on nerve growth factor, EGF was isolated from the submandibular glands of male mice after observations of accelerated incisor eruption and eyelid opening in newborn mice injected with salivary gland extracts. This discovery, which earned Cohen the Nobel Prize in Physiology or Medicine in 1986, revealed EGF as a key regulator of epithelial growth and development. Structurally, human EGF is a 6-kDa single-chain protein with three intramolecular bonds that stabilize its compact fold, enabling precise interaction with the extracellular domain of , a 170-kDa transmembrane receptor. Upon binding, EGF induces dimerization and autophosphorylation of intracellular residues, activating downstream signaling cascades such as the RAS-RAF-MEK-ERK pathway for and the PI3K-AKT pathway for anti-apoptotic and cytoprotective effects. These mechanisms underscore EGF's physiological roles in embryonic development, tissue homeostasis, , and organ regeneration, including stimulation of migration and re-epithelialization in skin repair as well as modulation of gastrointestinal mucosal integrity. In clinical contexts, EGF has been applied since the late 1980s for therapeutic purposes, notably in topical formulations to accelerate healing of ulcers, burns, and corneal injuries, with demonstrated efficacy in promoting tissue regeneration across peripheral and gastrointestinal applications. However, dysregulation of the EGF-EGFR axis, often through overexpression or mutation, contributes to oncogenesis in various cancers, including , , and colorectal tumors, making it a prime target for targeted therapies such as inhibitors (e.g., ) and monoclonal antibodies (e.g., ). Ongoing research continues to explore EGF's potential in while addressing challenges like tumor-promoting risks in chronic applications.

Molecular properties

Primary structure

Epidermal growth factor (EGF) is initially synthesized as a large transmembrane precursor protein, pro-EGF, comprising 1,207 in s, with an N-terminal , an EGF , multiple EGF-like repeats, a juxtamembrane , a transmembrane region, and a cytoplasmic tail. Proteolytic processing of pro-EGF by enzymes such as metalloproteases and secretases releases the mature EGF polypeptide from the extracellular domain. The mature form of human EGF is a single-chain polypeptide of 53 , lacking additional post-translational modifications beyond bond formation. It has a calculated molecular weight of approximately 6.2 and an of about 4.6, contributing to its acidic nature and solubility properties. A key structural feature of mature EGF is the conserved EGF motif, which includes six residues that form three intramolecular bonds at positions 6–20, 14–31, and 33–42 (numbering from the of the mature protein). These bridges stabilize the protein into a compact structure with three loops—commonly referred to as the A, B, and C loops—essential for maintaining the bioactive conformation.

Biological sources and

Epidermal growth factor (EGF) is primarily produced in mammalian tissues such as the submandibular salivary glands, kidneys, (including ), and , with additional expression in lactating mammary glands and . In , the submandibular glands represent the richest source, containing up to 1000 ng/mg of EGF in males compared to 70 ng/mg in females, while in humans, salivary levels are lower and kidneys serve as the predominant site. EGF is detectable in bodily fluids including , , , , intestinal secretions, and , reflecting its tissue-specific production and secretion. EGF is synthesized as a large membrane-anchored precursor known as prepro-EGF, which consists of 1,207 amino acids in humans and 1,217 in mice, encoded by a 24-exon gene located on chromosome 4q25–q27 in humans and chromosome 3 in mice. The prepro-EGF undergoes N-glycosylation and features two hydrophobic regions: a signal peptide for translocation into the endoplasmic reticulum and a transmembrane anchor that tethers it to the cell membrane. Mature EGF, a 53-amino-acid polypeptide, is liberated from this precursor through proteolytic cleavage at specific sites, such as Arg-Asn and Arg-His bonds, primarily by zinc metalloproteases; in the kidneys, much of the prepro-EGF remains membrane-bound rather than being fully processed. Regulation of EGF expression exhibits tissue-specific and species-dependent patterns, with transcriptional control influenced by hormones and physiological states. In submandibular glands, androgens and adrenergic stimuli like upregulate EGF synthesis and storage in granular cells of the tubular ducts. In humans, EGF release from salivary glands, , and is modulated by neurohormonal mechanisms, while urinary EGF levels increase during , peaking at 19–22 weeks .

Biological functions

Cellular effects

Epidermal growth factor (EGF) primarily acts on epithelial cells to stimulate , , and , thereby supporting maintenance and repair in various organs. In the skin, EGF promotes the and of , facilitating epidermal regeneration and wound closure. Similarly, in the , EGF enhances epithelial cell and , which are critical for corneal and re-epithelialization following injury. In the , EGF drives the and of intestinal epithelial cells, aiding in the repair of mucosal barriers and preventing under stress conditions. Beyond proliferative effects, EGF promotes in specific epithelial contexts. For example, in the , EGF receptor activation in suprabasal induces late terminal markers, such as involucrin and loricrin expression, contributing to the maturation of the epidermal barrier. EGF also exerts effects on mesenchymal cells, particularly fibroblasts, where it stimulates proliferation and enhances production, including synthesis, to support tissue remodeling and in connective tissues. These cellular responses to EGF exhibit concentration dependence, with low nanomolar concentrations (e.g., 0.1–1 ng/mL) predominantly driving and in epithelial and mesenchymal cells, while higher concentrations (e.g., 10–100 ng/mL) favor in contexts like keratinocyte maturation.

Mechanism of action

Epidermal growth factor (EGF) exerts its effects by binding with high affinity to the (), a located on the cell surface. This binding occurs primarily at the extracellular domain of EGFR, with a in the nanomolar range, leading to a conformational change that promotes receptor dimerization, either as homodimers or heterodimers with other family members. Upon dimerization, the intracellular kinase domains of the EGFR monomers come into proximity, enabling trans-autophosphorylation of specific residues in the C-terminal tail, such as Tyr1068 and Tyr1173. This autophosphorylation activates the intrinsic activity of the receptor, transforming these phosphotyrosine sites into high-affinity docking platforms for SH2-domain-containing adaptor proteins, including and Shc. The recruitment of and Shc to these docking sites initiates downstream signaling cascades by linking the receptor to guanine nucleotide exchange factors like , which activate and subsequently the MAPK/ERK pathway to promote . Concurrently, these adaptors facilitate the activation of the PI3K/Akt pathway, which supports cell survival and growth. Following activation, the EGF-EGFR complex undergoes clathrin-mediated , internalizing the ligand-receptor pair into early endosomes. This process regulates the duration and magnitude of signaling by sorting the complex toward lysosomal degradation, thereby attenuating receptor activity and preventing prolonged stimulation.

EGF family and related domains

Family members

The epidermal growth factor (EGF) family consists of a group of structurally related peptide ligands that bind to and activate the (EGFR), with the core members being transforming growth factor alpha (TGF-α), amphiregulin (AREG), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), epiregulin (EREG), and epigen (EPGN). These ligands, alongside EGF itself, represent the primary endogenous activators of in mammals. All EGF family members share a conserved EGF-like motif, typically comprising approximately 40-50 amino acids with six cysteine residues that form three intramolecular disulfide bonds, enabling receptor binding through a characteristic beta-sheet structure. This motif allows them to interact with EGFR's extracellular domain, though with varying affinities; for example, EGF, TGF-α, and BTC bind with high affinity (Kd ~0.1-1 nM), while epiregulin exhibits lower affinity (Kd ~1-10 nM). Distinct structural features differentiate individual members: HB-EGF possesses an N-terminal heparin-binding domain rich in basic residues, which promotes association with proteoglycans in the . TGF-α, in contrast, features a more compact structure optimized for stable membrane association during early developmental signaling. The EGF family demonstrates remarkable evolutionary across mammals, with the EGF-like motifs retaining over 70% sequence identity between and orthologs, reflecting their essential roles in conserved physiological processes.

EGF-like domains

EGF-like domains are conserved protein motifs typically comprising 30 to 40 , characterized by six invariant residues that form three intramolecular bonds with a specific pattern of 1-3, 2-4, and 5-6. This features the cysteines spaced by variable loops, often including conserved glycine and aromatic residues that contribute to the domain's stability and folding. Some variants, known as calcium-binding EGF-like domains, incorporate additional motifs such as D-x-D/N-x-D/N-x-x-x-x-Y/F to coordinate Ca²⁺ ions, enhancing structural rigidity. These domains are prevalent in a wide of proteins unrelated to the EGF family ligands, serving diverse roles in protein-protein interactions. In receptors, tandem repeats of up to 36 EGF-like domains form the extracellular stalk, facilitating cell-cell signaling critical for developmental processes like and somitogenesis. In fibrillin-1, an , 47 EGF-like domains organize into tandem s that support assembly and formation in connective tissues. Similarly, in blood factors such as VII, IX, X, , and , EGF-like domains mediate binding to membranes or other proteins, essential for hemostatic regulation. Beyond receptor activation, the functional diversity of EGF-like domains encompasses , recognition, and signaling modulation in developmental and homeostatic contexts. For instance, in the pathway, these domains enable ligand-induced conformational changes that propagate intracellular signals for . In cascades, they promote activation and complex formation on cell surfaces. High-resolution crystal structures of isolated EGF-like domains, such as that from the first module of human (PDB: 1EDM), reveal a compact fold dominated by a major N-terminal two-stranded antiparallel β-sheet, followed by a loop region and a minor C-terminal β-sheet, all stabilized by the bridges and, in calcium-binding variants, by a coordinated Ca²⁺ ion. This architecture, conserved across diverse proteins, underscores the domain's versatility in mediating specific intermolecular contacts while maintaining structural integrity in extracellular environments.

Molecular interactions

Receptor binding

Epidermal growth factor (EGF) binds to the extracellular region of its primary receptor, the (, also known as 1), with high affinity, characterized by a (Kd) of approximately 1 nM. This binding exhibits specificity for over other ErbB family receptors (2–4), with EGF showing low-affinity interactions (Kd > 100 nM) with ErbB3 and ErbB4, and no direct high-affinity binding to the orphan ErbB2. The binding interface is located primarily on domains I and III of the extracellular domain, where EGF docks in a cleft formed by these leucine-rich repeats. Specifically, the three disulfide-constrained loops of EGF—A (N-terminal), B (central), and C (C-terminal)—mediate the key contacts: A and C primarily interact with domain I via hydrophobic and hydrogen bonding residues such as Leu14, Leu47, and Tyr13 on EGF with residues like Ile21 and Phe357, while B engages domain III through residues like Arg41 on EGF contacting 's Leu382 and Asp355. These interactions position EGF to stabilize a high-affinity 1:1 complex, with the overall structure revealing a curved arrangement of domains I–III around the . Upon binding, EGFR undergoes a significant conformational shift from a tethered, autoinhibited state—where domain II interacts intramolecularly with domain IV, sequestering the dimerization interface—to an extended conformation that exposes the domain II dimerization arm for subsequent receptor dimerization. This transition enhances affinity and primes the receptor for , as the extended form binds EGF ~1000-fold more tightly than the isolated low-affinity site on domain III alone. Members of the EGF family, such as transforming growth factor-α (TGF-α) and , competitively inhibit EGF binding by occupying the same I and III interface, though with varying potencies; for instance, TGF-α exhibits comparable affinity (Kd ~0.5–1 nM) but induces slightly different domain rearrangements. This competition underscores the shared binding specificity within the family while highlighting subtle differences in loop-receptor contacts that influence activation efficiency.

Downstream signaling

Upon ligand-induced dimerization and autophosphorylation of the (), multiple tyrosine residues serve as docking sites for downstream effectors, initiating a network of branching signaling cascades that regulate diverse cellular processes. The Ras-Raf-MEK-ERK pathway represents a central arm for promoting and transcription. Phosphorylated recruits the adapter protein bound to , a that activates by facilitating GTP loading; active then sequentially phosphorylates and activates Raf, MEK1/2, and ERK1/2 kinases. ERK translocates to the , where it phosphorylates transcription factors such as AP-1 (c-Fos/c-Jun), inducing expression of and other genes that drive G1/S progression. A parallel branch involves phospholipase C-γ (PLCγ), which binds to phosphorylated tyrosines like Y992 and Y1173 on , leading to of (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG); IP3 triggers intracellular calcium release, activating (PKC) isoforms that support cytoskeletal reorganization and . Additionally, signal transducer and activator of transcription (STAT) proteins, particularly and , are activated through direct by or indirectly via kinases, dimerizing and translocating to the to transcribe anti-apoptotic genes such as and Mcl-1, thereby inhibiting . Another major pathway is the PI3K-AKT cascade, where phosphorylated EGFR recruits the p85 subunit of phosphoinositide 3-kinase (PI3K) either directly or via adapters like Gab1, leading to activation of PI3K and production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 recruits and activates AKT (protein kinase B), which promotes cell survival, growth, and metabolism by inhibiting pro-apoptotic proteins like FOXO and BAD, and activating mTOR for protein synthesis. These pathways exhibit crosstalk with other signaling modules, notably integrins, which is particularly evident in wound healing contexts. For instance, EGF-stimulated EGFR signaling promotes the phosphorylation and mobilization of α6β4 integrins from hemidesmosomes to lamellipodia in keratinocytes, enhancing adhesion to laminin-332 and coordinating focal ECM degradation via matrix metalloproteinases to facilitate directed migration during re-epithelialization. Negative regulation ensures signaling fidelity and prevents excessive activation; protein tyrosine phosphatase 1B (PTP1B) dephosphorylates specific EGFR residues (e.g., Y845), attenuating kinase activity, while Sprouty proteins form feedback loops by binding Grb2 and inhibiting Ras activation in the ERK pathway. The functional outcomes of EGFR signaling are modulated by the duration and amplitude of pathway activation. Sustained ERK , often resulting from prolonged EGFR stimulation, downregulates antiproliferative genes and commits cells to , whereas transient ERK activation is insufficient for full mitogenic responses and may instead promote or quiescence.

Physiological and pathological roles

Role in development and

Epidermal growth factor (EGF) plays a pivotal role in embryonic development by regulating key . In closure, EGF receptor () signaling promotes epithelial and migration at the leading edge of the developing , ensuring proper during late in mice. Disruption of this pathway, as seen in EGFR-deficient models, results in failure of eyelid closure, leading to the eye-open-at-birth . Similarly, EGF influences formation by modulating epithelial-mesenchymal interactions during embryogenesis; it supports the of follicular structures through autocrine and paracrine mechanisms involving EGFR ligands. In development, EGF is essential for branching , where it drives epithelial and patterning in the embryonic bud, as evidenced by reduced branching and impaired epithelial in EGFR-null embryos. In adult , EGF maintains the and turnover of various epithelia. Within the , EGF regulates epithelial and suppresses constitutive cell extrusion, thereby preserving mucosal barrier function and preventing excessive shedding that could compromise intestinal . This is achieved through EGFR-mediated MEK-ERK signaling, which balances cell renewal in the crypt-villus axis. In the , basal levels of EGF in tear fluid sustain EGFR signaling to support epithelial , , and barrier , ensuring ocular surface under normal physiological conditions. EGF also contributes to endogenous tissue repair processes without inducing in healthy contexts. During , EGF enhances re-epithelialization by stimulating and at wound edges, facilitating rapid closure while preserving balance. In mucosal tissues, such as the oral or gastrointestinal lining, EGF similarly promotes epithelial sheet and restitution, restoring post-minor damage through localized activation. Studies on EGFR knockout mice underscore these roles, revealing developmental defects that highlight EGF's necessity. EGFR-null mice exhibit open eyelids at birth, wavy hair due to impaired follicle cycling, and defective lung branching with reduced alveolar septation, all of which demonstrate the ligand's critical function in epithelial morphogenesis and homeostasis. These phenotypes arise from disrupted EGFR signaling in epithelial compartments, confirming EGF's non-redundant contributions without compensatory mechanisms from other pathways.

Role in disease

Dysregulation of epidermal growth factor (EGF) signaling, particularly through overexpression or aberrant activation of its receptor , plays a central role in various pathological conditions, most notably cancer and . In cancer, EGFR amplification is a common oncogenic driver, occurring in approximately 40-50% of glioblastomas, where it promotes tumor cell , invasion, and resistance to . Similarly, EGFR amplification is reported in 5-20% of non-small cell cancers (NSCLC), often co-occurring with mutations and enhancing proliferative signaling that contributes to tumor progression. These alterations sustain downstream pathways like /MAPK, leading to uncontrolled and poor prognosis in affected patients. In fibrotic diseases, sustained EGF/EGFR signaling exacerbates tissue remodeling by promoting excessive deposition. In liver fibrosis, ligands such as heparin-binding EGF-like growth factor (HB-EGF) activate on hepatic stellate cells, driving their proliferation and fibrogenic activity, which can progress to if unchecked. Likewise, in lung fibrosis, hyperactive signaling mediates a maladaptive response to injury, increasing activation and collagen production, as seen in where elevated ligands correlate with disease severity. Beyond cancer and , EGF dysregulation contributes to other disorders involving aberrant epithelial responses. In , EGFR overexpression in lesional drives hyperproliferation and , with ligands like TGF-α and HB-EGF amplifying proinflammatory production such as GM-CSF. Conversely, impaired EGF signaling delays in ; hyperglycemia suppresses EGFR and downstream migration pathways in epithelial cells, resulting in chronic ulcers and reduced formation. Recent insights as of 2025 highlight EGF/EGFR's involvement in disrupting homeostasis during aging and post-viral repair. Declining EGF levels with age impair epithelial regeneration, contributing to frailty in and organ maintenance, while overactive EGFR signaling exacerbates in aging tissues. In post-viral contexts, such as COVID-19-induced lung damage, elevated EGFR expression correlates with severity in affected lungs, promoting persistent scarring through sustained inflammatory and fibrotic responses observed in studies.

Clinical applications

Wound healing and regeneration

Epidermal growth factor (EGF) plays a pivotal role in therapeutic applications for , particularly through recombinant EGF (rhEGF) formulations that accelerate repair in and acute wounds. Topical rhEGF has demonstrated in treating ulcers, where meta-analyses of randomized controlled trials indicate significant reductions in wound size and healing time compared to standard care, with complete closure rates improving by up to 20-30% in treated patients. Intralesional administration of rhEGF, as in the formulation Heberprot-P, further enhances formation and epithelialization in neuropathic ulcers, showing safety and in III trials across multiple countries. For wounds, preclinical studies in animal models have shown that topical rhEGF ointments promote faster re-epithelialization in partial-thickness burns, with reduced healing duration by 25-40% and decreased scarring when applied early post-injury; clinical trials support its use in promoting in partial-thickness burns. These effects stem from EGF's stimulation of and , making it a valuable adjunct in managing non-healing wounds resistant to conventional therapies. In , rhEGF and ointments are utilized to expedite corneal epithelial recovery following abrasions or surgical trauma. Clinical trials have shown that rhEGF promotes rapid re-epithelialization in persistent epithelial defects, reducing healing time from weeks to days and alleviating symptoms like pain and , with minimal adverse effects such as transient irritation. Combined with , rhEGF drops further improve outcomes in post-cataract dry eye with corneal involvement, enhancing tear film stability and epithelial integrity. This application leverages EGF's ability to activate corneal stem cells, positioning it as a non-invasive option for superficial ocular surface injuries. For bone regeneration, EGF incorporated into biomaterial scaffolds supports fracture healing by boosting osteoblast proliferation and differentiation. In vitro and animal studies demonstrate that EGF-loaded collagen scaffolds increase bone mineral density and accelerate callus formation in critical-sized defects, with enhanced expression of osteogenic markers like alkaline phosphatase. When combined with bone morphogenetic proteins, EGF synergistically promotes early-phase osteogenesis, improving scaffold integration and mechanical strength in preclinical models of long-bone fractures. In dermatological cosmetics, rhEGF serums have gained prominence for anti-aging by stimulating dermal synthesis and epidermal renewal. Peer-reviewed studies indicate improvements in depth and skin elasticity after 4-8 weeks of use through activation, though long-term safety data emphasize controlled dosing to avoid potential overstimulation and risks such as tumor . These topical products, often derived from bioengineered sources, offer a non-invasive approach to counteract ; the U.S. FDA classifies EGF as a but notes the need for further safety evaluation in long-term applications.

Cancer therapy and other uses

Epidermal growth factor receptor (EGFR) inhibitors have become cornerstone therapies in , particularly for cancers harboring EGFR mutations or overexpression. Monoclonal antibodies such as target the extracellular domain of , blocking ligand binding and dimerization, and are approved for use in metastatic (mCRC) with wild-type and in combination with or for locally advanced head and neck (HNSCC). In non-small cell (NSCLC), inhibitors (TKIs) like (first-generation) and (third-generation) inhibit the intracellular kinase domain, demonstrating superior efficacy in EGFR-mutant advanced NSCLC; , for instance, improved compared to earlier TKIs in first-line settings. These agents exploit EGFR's role in tumor proliferation and survival, with response rates up to 70-80% in EGFR-mutant NSCLC. Acquired resistance limits long-term efficacy of TKIs. The T790M secondary in 20 of accounts for approximately 50% of resistance cases to first- and second-generation TKIs like , sterically hindering inhibitor binding while preserving ATP access. MET gene represents another key mechanism, occurring in 5-20% of resistant cases, often mutually exclusive with T790M, and activates parallel signaling pathways to bypass inhibition. In , T790M is rarer but has been reported, occasionally responding to . Recent advances address resistance through next-generation inhibitors and combinations. , effective against T790M, is now standard first-line therapy for EGFR-mutant NSCLC, but resistance emerges via MET amplification or other alterations. As of 2025, combinations like plus platinum-based (e.g., and ) have extended median overall survival to nearly four years in advanced EGFR-mutant NSCLC, based on phase III FLAURA2 trial data, with FDA approval for this regimen. Ongoing studies explore MET inhibitors alongside for MET-driven resistance. Beyond NSCLC and , anti-EGFR therapies are integral to HNSCC management. Cetuximab, combined with radiotherapy, improves locoregional control and survival in locally advanced HNSCC, with phase III evidence supporting its use over in certain settings. In recurrent or metastatic HNSCC, plus platinum-fluorouracil extends overall survival by about 2.7 months. Emerging non-oncologic applications leverage inhibition for dermatologic conditions. Investigational topical agents, such as BRAF-inhibiting gels, are being explored to mitigate acneiform rashes—a common of systemic inhibitors—by modulating downstream signaling without systemic interference; for example, a topical BRAF formulation (LUT014) showed rapid improvement in severity within 28 days in phase II trials. Similar approaches, including biologics like , are under investigation for managing -induced eczematous reactions, though clinical data remain preliminary. In glioblastoma, bispecific antibodies targeting EGFR variants offer promising investigational avenues. A 2025 first-in-human phase I trial of an EGFRvIII × CD3 T-cell bispecific antibody in newly diagnosed EGFRvIII-positive glioblastoma demonstrated safety and tolerability up to the maximum tested dose when administered post-standard therapy, with evidence of immune activation and preliminary antitumor activity in maintenance settings.

History

Discovery

Epidermal growth factor (EGF) was first identified in 1962 by biochemist Stanley Cohen at , who isolated it from extracts of the mouse while investigating . Cohen observed that crude preparations from these glands, when injected into newborn mice, induced precocious development, specifically accelerating eyelid opening from the normal 12–14 days to 6–7 days and incisor from 8–10 days to 5–6 days. This protein, initially termed the "tooth-lid factor," was purified as a heat-stable, acidic polypeptide that retained activity after extensive and precipitation steps. Further characterization revealed EGF's role in promoting epithelial cell growth. In 1965, Cohen developed an organ culture assay using embryonic chick skin, where purified EGF fractions directly stimulated epidermal proliferation, thickening the corneal epithelium and increasing DNA content without affecting dermal components. The protein was confirmed as an acidic fraction (isoelectric point around 4.6) through chromatography and electrophoresis, distinguishing it from nerve growth factor and establishing its specificity for epithelial tissues. These early studies highlighted EGF's potent mitogenic effects at nanogram levels. Cohen's foundational work on EGF, alongside Rita Levi-Montalcini's discovery of , earned them the 1986 in Physiology or Medicine for elucidating mechanisms controlling cell and organ development. Early bioactivity assays evolved to include measurements, such as stimulation of in quiescent Swiss 3T3 mouse fibroblasts, where EGF induced thymidine incorporation after a 14–15 hour prereplicative phase, providing a quantitative readout for purity and potency. This cell-based assay became instrumental in refining EGF preparations during the 1970s.

Key developments

Following the of epidermal growth factor (EGF) in 1962, researchers rapidly advanced the understanding of its structure and function. In 1972, the primary amino acid sequence of EGF was determined, identifying it as a 53-residue polypeptide stabilized by three intramolecular bonds essential for its . This structural elucidation enabled subsequent studies on its synthesis and modifications, with confirmation of the disulfide pairings in 1973. A major breakthrough occurred in the late 1970s and early 1980s with the identification and characterization of the EGF receptor (). Binding studies in 1973 demonstrated specific, high-affinity interactions between EGF and cell surface receptors, laying the groundwork for receptor isolation. By 1980, it was established that EGF binding activates a activity in the receptor, marking the first link between growth factor signaling and on residues—a discovery that illuminated broader mechanisms in . The receptor itself was purified in 1981 as a 170-kDa transmembrane . Cloning of the in 1984 represented a pivotal milestone, allowing detailed molecular analysis. Axel Ullrich and colleagues sequenced the full-length human EGFR cDNA, revealing a 1,210-amino acid precursor with extracellular ligand-binding, transmembrane, and intracellular domains, and noting in A431 cells. Concurrently, John Downward and coworkers demonstrated between EGFR and the v-erbB , suggesting oncogenic potential and establishing EGFR as a proto-oncogene. The EGF itself was cloned in 1983, showing it encodes a large precursor protein processed into the mature form. Advances in signaling pathways followed in the and , defining EGFR's role in mitogenesis. The receptor's dimerization upon EGF binding was confirmed, leading to autophosphorylation and activation of downstream cascades like the /Raf/MEK/ERK pathway, critical for and . By the mid-, cross-talk with other pathways, including PI3K/Akt and PLCγ, was delineated, highlighting EGFR's integration into complex networks regulating and . Clinically, EGF's therapeutic potential emerged in the late . A randomized trial demonstrated that topical recombinant human EGF accelerated in normal and diabetic patients by promoting epithelialization and formation. This paved the way for approvals, such as in in 2006 for diabetic foot ulcers. In oncology, EGFR's overexpression in tumors led to targeted therapies; the 2004 discovery of activating EGFR mutations in non-small cell correlated with sensitivity to inhibitors like , transforming treatment paradigms. Recent developments include engineered EGF variants for enhanced specificity and reduced off-target effects. For instance, tethered EGF presentations in biomaterials improved differentiation and outcomes in preclinical models by 2007. Ongoing research as of 2025 explores EGF in , such as corneal repair through preclinical and early clinical studies, while phase III trials have confirmed efficacy in accelerating healing for ulcers. Advancements in EGFR-targeted therapies, including next-generation inhibitors, continue to evolve for .