Extracellular signal-regulated kinases: ERKs in progress.

Hormones and other agents with receptors that signal through known heterotrimeric G proteins control the production and release of second messengers (i.e., cAMP, diacylglycerol, intracellular calcium) (Gilman, 1987). These messengers modulate cellular functions in part due to altered protein-serine/threonine phosphorylation catalyzed by second messenger-dependent protein kinases. Many growth factors and cytokines also lead to pronounced changes in protein-serine/threonine phosphorylation. They have some ability to utilize phospholipidand calcium-dependent pathways, but second messenger-independent protein-serine/threonine phosphorylation is required to elicit their full spectrum of actions. The early steps in signal transduction mechanisms triggered by their receptors to regulate second messenger-independent serine/threonine phosphorylation are unknown. Notable among these factors are the considerable number whose receptors contain or associate with tyrosine kinases (Rosen et al., 1983; Hunter and Cooper, 1985; Veillette et al., 1988; Yarden and Ullrich, 1988; Squinto et al., 1991). Thus, a critical unsolved problem in understanding cellular regulation is how tyrosine kinases induce the major changes in phosphorylation that occur downstream of the receptor on serine/threonine residues. In the last 5 y the insulinand growth factor-stimulated phosphorylation of ribosomal protein S6 on serine residues has been the object of intense scrutiny in the dissection and reconstruction of signaling mechanisms triggered by factors that activate tyrosine kinases (Erikson and Maller, 1986; Blenis et al., 1987; Ballou et al., 1988; Gregory et al., 1989; Ahn et al., 1990; Price et al., 1990; Chen et al., 1 991 ). Despite the fact that the precise effects of S6 phosphorylation on ribosome function are unclear, the increased phosphorylation of S6 is a rapid consequence of insulin and growth factor action that has been exploited to gain insights into mechanisms by which growth factors regulate serine/threonine phosphorylation networks (Rosen etal., 1981; NovakHofer and Thomas, 1984; Tabarini et al., 1985; Cobb, 1986; Erikson and Maller, 1986; Pelech and Krebs, 1987; Bannerjee et al., 1990). The complexity of protein kinase networks, involved not only in S6 phosphorylation but also in the regulation of phosphorylation of other proteins (Flotow et al., 1990), exceeds the expectations of 5 y ago. Compounding the complexity, a large fraction of cellular proteins, perhaps as many as 250/o of the total (Blackshear, personal communication), are phosphorylated and many of these phosphorylations influence protein function. Nevertheless, significant progress has been made in identifying enzymes involved in S6 phosphorylation. A second protein kinase cascade, in addition to the cascade originally discovered by Krebs and associates in 1968 in which cAMP-dependent protein kinase activates phosphorylase kinase (DeLange et al., 1968), has been found. This newly identified cascade (Figure 1) includes three activities acting sequentially: one type of S6 kinase known as rsk for ribosomal protein S6 kinase (Erikson and Maller, 1986; Jones et al., 1988), a kinase that phosphorylates this S6 kinase (Sturgill et al., 1988), and an activator of this S6 kinase kinase (Ahn et al., 1991). Each of these components will be discussed below. Recently, two enzymes that are S6 kinase kinases and a third related kinase have been cloned and named extracellular signal-regulated kinases (ERKs)1 1, 2, and 3 (Boulton et al., 1 990b, 1991 b) to reflect the great diversity of signals that stimulate them (Table 1). These kinases have been referred to in the literature not only as S6 kinase kinases, but also as