Menin encoded by the multiple endocrine neoplasia type 1 (MEN1) gene is associated with chromatin and the nuclear matrix and exerts multiple biological functions including regulation of cell proliferation and adhesion. Men1 mutations increase the likelihood of lung cancer development in mice. Menin expression is reduced in certain human non-small cell lung cancer cells, and reduction of menin is closely correlated with increased lung cancer metastasis to lymph nodes. However, it is poorly understood whether menin affects migration of lung cancer cells. In this study, we show that menin-regulated A549 lung cancer cell migration, which was mediated by growth factor pleiotrophin (PTN) and its cell surface receptor, protein tyrosine phosphatase beta/zeta (RPTP Β/ζ). Ectopic menin expression significantly repressed PTN transcription, but indirectly inhibited RPTP Β/ζ expression through repressing PTN expression. Further studies revealed that menin-regulated cell migration through PTN/RPTP Β/ζ, in conjunction with integrin α v Β 3, focal adhesion kinase, phosphatidylinositol 3-kinase and phosphorylated extracellular signal regulated kinase 1/2. These findings provide mechanistic insights into the molecular basis for menin/PTN-mediated regulation of A549 lung cancer cell migration. © 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10.