We have previously shown that insulin-like growth factor (IGF) binding protein- 5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that IGFBP-5 induction of extracellular matrix occurs independently of IGF-I, and results from IGFBP-5 activation of MAPK signaling, which facilitates the translocation of IGFBP-5 to the nucleus. We examined the effects of IGFBP-5 on early growth response (Egr)-1, a transcription factor that is central to growth factor-mediated fibrosis. Egr-1 was up-regulated by IGFBP-5 in a MAPK-dependent manner and bound to nuclear IGFBP-5. In fibroblasts from Egr-1 knockout mice, induction of fibronectin by IGFBP-5 was abolished. Expression of Egr-1 in these cells rescued the extracellular matrix-promoting effects of IGFBP-5. Moreover, IGFBP-5 induced cell migration in an Egr-1-dependent manner. Notably, Egr-1 levels, similar to IGFBP-5, were increased in vivo in lung tissues and in vitro in primary fibroblasts of patients with pulmonary idiopathic fibrosis. Taken together, our findings suggest that IGFBP-5 induces a fibrotic phenotype via the activation of MAPK signaling and the induction of nuclear Egr-1 that interacts with IGFBP-5 and promotes fibrotic gene transcription.