title: Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression.
abstract: The neurofibromatosis 2 (NF2) tumor suppressor protein, merlin, functions as a negative growth regulator; however, the molecular mechanisms that underlie merlin regulation remain elusive. Recent studies have implicated merlin phosphorylation in regulating merlin subcellular localization and growth suppression. P21-activated kinase (PAK), a downstream target of Rac1/Cdc42, directly phosphorylates merlin at Serine 518. In this report, we show that PAK2 directly phosphorylates wild-type merlin, whereas merlin truncation mutants with impaired GST-amino-terminal domain (N-term or NTD)/GST-carboxy-terminal domain (C-term or CTD) intramolecular association exhibit impaired S518 phosphorylation. We directly demonstrate that PAK2 phosphorylation impairs merlin N-term/C-term binding in vitro and in vivo. Lastly, we show that PAK2 phosphorylation impairs the ability of merlin to bind to two interacting proteins, CD44 and hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), both critical for merlin growth suppression. These observations suggest that merlin S518 phosphorylation directly modulates merlin intramolecular and intermolecular associations important for the ability of merlin to function as a tumor suppressor.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.forename: Ezequiel I
authors.initials: EI
authors.lastname: Surace
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Haipek
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation; D016518:Neurofibromatosis 2 / Q000235:genetics* / Q000378:metabolism; D025581:Neurofibromin 2 / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism*; D054462:p21-Activated Kinases; D013049:Spectrin
chemical_list: D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D018960:Hyaluronan Receptors; D008840:Microfilament Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D054462:p21-Activated Kinases; D013049:Spectrin; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C515907:PAK2 protein, human; C515910:Pak2 protein, rat