The role of extracellular proteases in cell proliferation and differentiation.

Proteases have been shown to be capable of inducing two of the most fundamental biologic processes: mitogenesis and cellular differentiation. Their proteolytic activity has been the most widely studied enzymatic activity implicated in inducing these processes. Protease induction of mitogenesis is a major system for studying the control of this process and studies of possible transmembrane signals have been initiated. Proteases have only recently begun to be used as tools for probing the induction of differentiation, but at least three cell line systems have been studied. Extracellular proteases such as thrombin may play physiologic roles in inducing mitogenesis in vivo as suggested by several laboratories. Although the amount of data bearing on the similar possibility of the induction of differentiation by extracellular proteases is negligible, it remains a possibility. For example, macrophages not only have surface-bound proteases (6), but also release proteases (261, 308) as well as cytokines. Any of these agents, individually or in combination, may play a role in inducing erythroid differentiation in vivo and may provide a raison d'etre for the "blood islands" consisting of erythroblasts surrounding a "nurse" macrophage which are so frequently seen in bone marrow.