The extracellular regulation of growth factor action.

The concept that growth factors act as autocrine and paracrine regulators of cell growth and differentiation was introduced over a decade ago (Sporn and Todaro, 1980). Since then significant advances have been made in understanding the regulation of growth factor expression and interaction with high affinity plasma membrane receptors. More recently, structural analysis and in vitro experiments suggest that regulatory mechanisms other than growth factor expression and receptor binding dominate growth factor action. These data demonstrate that most growth factors do not simply diffuse passively from the site of their release to interact with the nearest cell surface receptor. Rather, many of these proteins contain structural features that foster their interaction with other molecules within the extracellular environment. These interactions confine the action of the growth factor to an appropriate place and time. Thus, the specificity of growth factor signaling is derived not only from its binding to cell surface receptors but also through critical interactions with other components of the extracellular environment. In this review we will describe recently appreciated mechanisms involved in the nonreceptor mediated extracellular regulation of growth factor activity.