Specificity within the EGF family/ErbB receptor family signaling network David J. Riese II and David F. Stern* Summary Recent years have witnessed tremendous growth in the epidermal growth factor (EGF) family of peptide growth factors and the ErbB family of tyrosine kinases, the receptors for these factors. Accompanying this growth has been an increased appreciation for the roles these molecules play in tumorigenesis and in regulating cell proliferation and differentiation during development. Consequently, a signifi- cant question has been how diverse biological responses are specified by these hormones and receptors. Here we discuss several characteristics of hormone- receptor interactions and receptor coupling that contribute to specificity: 1) a single EGF family hormone can bind multiple receptors; 2) a single ErbB family receptor can bind multiple hormones; 3) there are three distinct functional groups of EGF family hormones; 4) EGF family hormones can activate receptors in trans, and this heterodimerization diversifies biological responses; 5) ErbB3 requires a receptor partner for signaling; and 6) ErbB family receptors differentially couple to signaling pathways and biological responses. BioEssays 20:41–48, 1998.  1998 John Wiley & Sons, Inc. INTRODUCTION The signaling network composed of the epidermal growth factor (EGF) family of hormones and their receptors regu- lates the proliferation and differentiation of many tissue types. Deregulation of this network is a significant factor in the genesis or progression of several human cancers, including neoplasms of the brain, lung, breast, ovary, pan- creas, and prostate. 1,2 These observations have spurred efforts to elucidate how this signaling network is regulated and coupled to physiological responses and how regulation and coupling are disrupted in malignancies. Efforts to characterize this signaling network also have been triggered by the observations that the EGF family peptides, called neuregulins (NRGs), play a significant role in neural development and function. Neurons produce NRGs, whereas postsynaptic cells or cells associated with neurons (glia or Schwann cell precursors) express ErbB family recep- tors. NRG activates these receptors through a paracrine or juxtacrine mechanism. For example, NRGs produced by motor neurons induce acetylcholine receptor subunit tran- scription and protein synthesis in postsynaptic muscle cells, which express ErbB2 and ErbB3 and possibly EGFR and ErbB4. 3 Furthermore, NRGs expressed from sensory neuron axons stimulate Schwann cell proliferation and may promote the differentiation of neural crest cells into Schwann cell precursors. 4 In general, patterns of ErbB3 and ErbB4 expres- Department of Pathology, Yale University, New Haven, CT. Contract grant sponsor: National Cancer Institute; Contract grant sponsor: United States Public Health Service; Contract grant numbers: CA-45708 and HD- 07149; Contract grant sponsor: United States Army Medical Research and Materiel Command; Contract grant numbers: DAMD-17-94-J-4476 and DAMD-17- 94-J-4036. Current address: David J. Riese II, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy and Pharmacal Sciences, West Lafayette, IN. *Correspondence to: David F. Stern, Department of Pathology, BML-342, Yale University School of Medi- cine, P.O. Box 208023, New Haven, CT 06520-8023. E-mail: Stern@Biomed.med.yale.edu Review articles BioEssays 20:41–48,  1998 John Wiley & Sons, Inc. BioEssays 20.1 41