The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the 'open' conformation and suppresses cell growth and motility

The neurofibromatosis 2 tumor suppressor protein, merlin or schwannomin, fu nctions as a negative growth regulator; however, its mechanism of action is not known. In an effort to determine how merlin regulates cell growth, we analyzed a recently identified novel merlin interactor, hepatocyte growth f actor-regulated tyrosine kinase substrate (HRS). We demonstrate that regula ted overexpression of HRS in rat schwannoma cells results in similar effect s as overexpression of merlin, including growth inhibition, decreased motil ity and abnormalities in cell spreading. Previously, we showed that merlin forms an intramolecular association between the N- and C-termini and exists in 'open' and 'closed' conformations, Merlin interacts with HRS in the unf olded, or open, conformation. This HRS binding domain maps to merlin residu es 458-557, Overexpression of C-terminal merlin has no effect on HRS functi on, arguing that merlin binding to HRS does not negatively regulate HRS gro wth suppressor activity. These results suggest the possibility that merlin and HRS may regulate cell growth in schwannoma cells through interacting pa thways.