The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho

Loss of the tumour-suppressor gene TSC1 is responsible for hamartoma develo pment in tuberous sclerosis complex (TSC), which renders several organs sus ceptible to benign tumours. Hamartin, the protein encoded by TSC1, contains a coiled-coil domain and is expressed in most adult tissues, although its function is unknown. Here we show that hamartin interacts with the ezrin-ra dixin-moesin (ERM) family of actin-binding proteins. Inhibition of hamartin function in cells containing focal adhesions results in loss of adhesion t o the cell substrate, whereas overexpression of hamartin in cells lacking f ocal adhesions results in activation of the small GTP-binding protein Rho, assembly of actin stress fibres and formation of focal adhesions. interacti on of endogenous hamartin with ERM-family proteins is required for activati on of Rho by serum or by lysophosphatidic acid (LPA). Our data indicate tha t disruption of adhesion to the cell matrix through loss of hamartin may in itiate the development of TSC hamartomas and that a Rho-mediated signalling pathway regulating cell adhesion may constitute a rate-limiting step in tu mour formation.