Fig. 4. Proposed model for merlin tumor suppressor function. In the growth permissive state (growth factor receptor ligand binding), ERM proteins and merlin are phosphorylated by a cascade of kinases stimulated by Rho and Rac1 activation. Activated ERM proteins associate with CD44 cytoplasmic tail and promote cell growth, survival and motility. `Open' phosphorylated merlin resides in an inactive conformation and may associate with ERM proteins. In the growth arrest state (high molecular weight hyaluronic acid binding to CD44 receptor), this protein kinase cascade is not activated and ERM proteins are not phosphorylated. Merlin, in the hypophosphorylated form, is `closed' and active. `Active' merlin interacts with CD44 to facilitate inhibition of cell growth and motility. ERM proteins in the `closed' conformation would be predicted to dissociate from the CD44 complex. GFR, growth factor receptor; HA, hyaluronic acid.