Proteolytic regulatory mechanisms in the formation of extracellular morphogen gradients

Growth factors are secreted into the extracellular space, where they encounter soluble inhibitors, extracellular matrix glycoproteins and proteoglycans, and proteolytic enzymes that can each modulate the spatial distribution, activity state, and receptor interactions of these signaling molecules. During development, morphogenetic gradients of these growth factors pattern fields of cells responsive to different levels of signaling, creating such structures as the branched pattern of airways and vasculature, and the arrangement of digits in the hand. This review focuses specifically on the roles of proteolytic enzymes and their regulators in the generation of such activity gradients. Evidence from Drosophila developmental pathways provides a detailed understanding of general mechanisms underlying proteolytic control of morphogen gradients, while recent studies of several mammalian growth factors illustrate the relevance of this proteolytic control to human development and disease. Birth Defects Research (Part C) 78:243–255, 2006. © 2006 Wiley-Liss, Inc.