GASTROENTEROLOGY 1995;108:564-580 Epidermal Growth Factor-Related Peptides and Their Relevance to Gastrointestinal Pathophysiology JOHN A. BARNARD,* R. DANIEL BEAUCHAMP,* WILLIAM E. RUSSELL,*'§ RAYMOND N. DUBOIS,§'11 and ROBERT J. COFFEY g'll Departments of *Pediatrics, §Cell Biology, and lIMedicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and tDepartment of Surgery and Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas G rowth factor biology has been one of the most excit- ing areas of gastroenterological research in recent years. Although many fundamental questions about growth factors and their relevance to the gastrointestinal tract remain unanswered and unexplored, the available data point to major clinical significance in a large number of gastrointestinal disorders. This report reviews the biol- ogy and significance of the epidermal growth factor (EGF) family, with particular emphasis on understanding the integrated function of the family and the relation- ships between family members in the context of gastroin- testinal physiology and pathophysiology. Introduction to Growth Factors Growth factors are proteins that control cell pro- liferation and modulate other cellular functions by bind- ing to specific, high-affinity cell surface membrane recep- tors. The biological effects of these molecules are apparent at extremely low concentrations, usually in the nanogram per milliliter range. Studies by Dr. Stanley Cohen and Dr. Rita Levi-Montalcini established the cor- nerstone of modern growth factor research nearly 30 years ago. Dr. Cohen's work is particularly germane to this review. He painstakingly purified from the mouse sub- maxillary gland a factor that caused precocious eyelid opening and early incisor eruption in newborn mice) Histopathologic analysis of the eyelids showed hyperpla- sia and keratinization of the epidermis; consequently, the purified activity was named "epidermal growth factor." In the years after this discovery, molecular pathways for biosynthesis and processing of EGF have been defined, the EGF receptor (EGFr) has been cloned and extensively characterized, a complex cascade of intracellular signals generated by binding of EGF to the EGFr has been described, and an intricate pattern of modulation of growth-related gene expression by EGF has been deline- ated (see Carpenter and Wahl 2 for a comprehensive re- view). Because this pioneering work on the biology of EGF has established a fundamental framework for the study and understanding of many other polypeptide hor- mones and basic cellular processes, Cohen was a core- cipient of the Nobel Prize in Medicine in 1986. The rapid rate of progress in growth factor biology has resulted in a nomenclature that is sometimes mis- leading and cumbersome. For example, it has become useful to categorize proteins with similar structure and function into "families"; however, for the most part, the existence of families is not reflected in the nomenclature of individual growth factors. The classification of the transforming growth factor (TGF) [~-related peptide family is an exception in that each newly discovered member is designated numerically, e.g., TGF-[~I, TGF- 132, and so on. Curiously, TGF-~ is related to TGF-ot only from a historical perspective. Other problems with nomenclature are also encountered. Although most "growth factors" stimulate cellular proliferation, an in- creasing number ofpolypeptides that inhibit cellular pro- liferation are being described. These inhibitory factors are also designated "growth" factors. Historically, a growth factor has been named on the basis of its most prominent biological activity or the activity that resulted in its discovery; however, subsequent work with most of these factors has resulted in the description of activities that belie the original name. For example, EGF was discovered and so named because it stimulated epithelial cell growth in the newborn mouse eyelid, but further studies showed that EGF is also a powerful mitogen for fibroblasts. Simi- larly, fibroblast growth factors are also potent mitogens for epithelial and endothelial cells. Some growth factors also show activities that are quite unrelated to cell growth, as evidenced by inhibition of gastric acid secre- tion by EGF. Nomenclature will likely remain problem- atic because of the rapidly evolving nature of the field. The various pathways by which polypeptide growth factors modulate cellular function deserve brief review. Abbreviations used in this paper: AR, amphiregulin;EGF, epidermal growth factor; EGFr, epidermal growth factor receptor; HB-EGF,hepa- rin-binding EGF-likegrowth factor; TGF, transforming growth factor. © 1995 by the American Gastroenterological Association 0016-5085/95/$3.00