title: The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the "open" conformation and suppresses cell growth and motility.
abstract: The neurofibromatosis 2 tumor suppressor protein, merlin or schwannomin, functions 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 factor-regulated tyrosine kinase substrate (HRS). We demonstrate that regulated overexpression of HRS in rat schwannoma cells results in similar effects as overexpression of merlin, including growth inhibition, decreased motility 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 unfolded, or open, conformation. This HRS binding domain maps to merlin residues 453-557. Overexpression of C-terminal merlin has no effect on HRS function, arguing that merlin binding to HRS does not negatively regulate HRS growth suppressor activity. These results suggest the possibility that merlin and HRS may regulate cell growth in schwannoma cells through interacting pathways.
authors: Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA. gutmannd@neuro.wustl.edu
authors: D H
authors: DH
authors: Gutmann
authors: C A
authors: CA
authors: Haipek
authors: S P
authors: SP
authors: Burke
authors: C X
authors: CX
authors: Sun
authors: D R
authors: DR
authors: Scoles
authors: S M
authors: SM
authors: Pulst
mesh_terms: D000818:Animals; D001665:Binding Sites; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D056827:Endosomal Sorting Complexes Required for Transport; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008579:Meningioma; D025581:Neurofibromin 2; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate