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

• Published in: Human molecular genetics Vol. 10; no. 8; pp. 825 - 834
• Main Authors: GUTMANN, David H, HAIPEK, Carrie A, BURKE, Stephen P, SUN, Chun-Xiao, SCOLES, Daniel R, PULST, Stefan M
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-04-2001; Oxford Publishing Limited (England)
• Subjects: Animals; Binding Sites; Biological and medical sciences; Cell Division; Cell Line; Cell Movement; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Endosomal Sorting Complexes Required for Transport; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Humans; Membrane Proteins - metabolism; Meningioma; Molecular and cellular biology; Neurofibromin 2; Phosphoproteins - genetics; Phosphoproteins - metabolism; Rats; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Human; Cell proliferation; Neurofibromatosis II; Regulation(control); Enzyme; Hepatocyte growth factor; Transferases; Molecular interaction; Protein-tyrosine kinase; Tumor suppressor gene
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/10.8.825

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.