S100A11, a member of the family of S100 proteins, is a dimmer, each monomer of which has two EF-hands. Expression of S100A11 is ubiquitous in various tissues at different levels, with a high expression level in the skin. We have analyzed functions of S100A11 mainly in normal human keratinocytes (NHK) as a model cell system of human epithelial cells. High Ca(2+) and transforming growth factor-β (TGF-β), two representative growth suppressors for NHK, need a common S100A11-mediated pathway in addition to unique pathways (NFAT1-mediated pathway for high Ca(2+) and Smad-mediated pathway for TGF-β) for exhibiting a growth inhibitory effect. S100A11 has another action point for growth suppression in NHK. Annexin A1 (ANXA1) complexed with S100A11 efficiently binds to and inhibits cytosolic phospholipase A2 (cPLA2), the activity of which is needed for the growth of NHK. On exposure of NHK to epidermal growth factor (EGF), ANXA1 is cleaved at 12Trp, and this truncated ANXA1 loses binding capacity to S100A11, resulting in maintenance of an active state of cPLA2. On the other hand, we found that S100A11 is actively secreted by NHK. Extracellular S100A11 acts on NHK to enhance the production of EGF family proteins, resulting in growth stimulation. These findings indicate that S100A11 plays a dual role in growth regulation, being suppressive in cells and being promotive from outside of cells.