The Role of Extracellular Proteases in Cell Proliferation and Differentiation

Abstract

Proteases play critical roles in a vast number of reactions that are important in regulating anabolic as well as catabolic cellular metabolism and, in addition, many extra- and intracellular physiologic functions (158, 165, 288). Although regulation of specific and general protein levels by catabolism was not as emphasized in early studies as that of the regulation of protein synthesis, this is now recognized as an error (4, 200). The importance of proteases in “molding” a final protein product by converting a zymogen, a pro-hormone, or a pro-growth factor to an active moiety, or by removing a signal peptide to have the protein “delivered” to the proper location, is clear (see Refs. 295, 338, 397). Specific examples include the activation of epidermal growth factor (EGF) by the proteolytic EGF-binding protein (123, 384) or the auto-proteolytic processing of pro-β nerve growth factor (NGF) to NGF by its own γ-subunit (142, 389). The importance of studying protease induction of cell proliferation and DNA synthesis is now recognized (see Refs. 265, 266 for earlier reviews) and it has also been suggested that proteases may act as growth factors for malignant cells (41, 254) or in wound healing (see Ref. 30). Proteases appear to be able to act as true growth factors and not simply in a process directed toward supplying nutrient amino acids, as carefully defined by Gospodarowicz and Moran (140), although the latter case has not been ruled out as an augmenting process.