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Cells of the retinal pigment epithelium (RPE) play major roles in metabolic functions, maintenance of photoreceptor function, and photoreceptor survival in the retina. They normally form a stable monolayer, but migrate during disease states. Although growth factors produced by the RPE cells primarily control these cellular events, how these factors are regulated in RPE cells remain largely unknown. Here we show that the basic–helix–loop-helix–leucine zipper microphthalmia-associated transcription factor (MITF), which plays central roles in the development and function of a variety of cell types including RPE cells, upregulates the expression of a multifunctional factor PEDF in RPE cells. Consequently, the upregulation of PEDF impairs microtubule assembly and thus inhibits RPE cell migration. Conversely, specific knockdown of PEDF partially rescues the impairment of microtubule assembly and cell migration …