Bone morphogenetic proteins (BMPs), 1 members of the transforming growth factor- superfamily, were originally identified by their novel activity to induce cartilage and bone formation in ectopic extraskeletal sites in vivo (1, 2). A number of studies have demonstrated that BMPs play essential roles in bone formation and bone cell differentiation; e.g. BMPs stimulate proteoglycan synthesis, alkaline phosphatase activity, collagen synthesis, and osteocalcin expression in chondroblasts/ osteoblasts (3-5). However, expression of BMPs (6 -8) and their receptors (9) in many tissues other than bone suggests that they are also involved in the regulation of many biological processes unrelated to bone formation. In accordance with this possibility, increasing evidence suggests a regulatory role for BMPs in early vertebrate embryogenesis such as in mesoderm induction, limb development, and hematopoietic formation (10 -14). Moreover, BMPs have drawn attention as possible regulators of central nervous system development; BMPs are expressed in multiple central nervous system regions throughout development (15)(16)(17). In this respect, we have recently demonstrated that BMP-2 acts as a neurotrophic factor; BMP-2 induces the neuronal differentiation of rat pheochromocytoma PC12 cells (18) and also promotes the survival and differentiation of striatal GABAergic neurons in culture (19).BMPs transduce their signals by binding to two different types of serine/threonine kinase receptor, type I and type II (20 -22). Upon ligand binding, type I and type II receptors form heteromeric receptor complexes. Then type I receptors are phosphorylated by type II receptors, and subsequent activation of the catalytic activity of type I receptor kinase is essential for BMP signaling. Although phosphorylation of Smad proteins by the activated type I receptor kinase was suggested to play an important role in the mediation of BMP signaling (20 -22), the precise cytoplasmic signaling pathway for BMPs through which it elicits its effects on the regulation of wide variety of biological processes remains largely unknown.We have recently shown that BMP-2 has the capacity to induce the neuronal differentiation of PC12 cells. Unlike NGF, however, BMP-2 did not induce the activation of MEK or 41-/ 43-kDa MAP kinases (ERK2 and ERK1, respectively) in these cells (18). MEK and ERK1/2 constitute a protein kinase cascade (the ERK cascade), which is one of the major cytoplasmic signaling pathways commonly activated in a wide variety of cells by diverse extracellular stimuli (23)(24)(25)(26). Activation of the cascade elicits a wide array of physiological responses such as cell division, differentiation, and secretion (23-26), and it has been reported that the activation of the cascade is necessary and sufficient for PC12 cell neuronal differentiation (27,28). However, our previous findings, which showed a clear distinction between the requirement for the activation of MEK and ERK1/2 and the ability of BMP-2 to induce PC12 cell neuronal differentiation (18), hav...