INVESTIGADORES
SURACE Ezequiel Ignacio
artículos
Título:
Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene
Autor/es:
EZEQUIEL I SURACE, CARRIE A HAIPEK AND DAVID H GUTMANN
Revista:
ONCOGENE
Editorial:
Nature Publishing Group
Referencias:
Año: 2004 p. 580 - 587
ISSN:
0950-9232
Resumen:
The neurofibromatosis 2 (NF2) tumor suppressor gene
product, merlin, belongs to the ezrinradixinmoesin
(ERM) subgroup of the Protein 4.1 family, which links
cell surface glycoproteins to the actin cytoskeleton.
Previous studies have suggested that phosphorylation of
merlin, similar to other ERM proteins, may regulate its
function. To determine whether merlin phosphorylation
has functional consequences for merlin suppression of cell
growth and motility, we generated doxycycline-regulatable
RT4 schwannoma cell lines that inducibly express
full-length merlin with mutations at two potential
phosphorylation sites (amino-acid residues S518 and
T576). Whereas a mutation at S518 that mimics
constitutive phosphorylation (S518D) abrogates the ability
of merlin to suppress cell growth and motility, the
S518A merlin mutant, which mimics nonphosphorylated
merlin, functions equivalently to wild-type merlin. Similar
mutations involving T576, the analogous phosphorylation
site in ERM proteins important for regulating their
function, had no effect. In contrast to other functionally
inactive missense merlin mutants, the regulated overexpression
of S518D merlin resulted in dramatic changes
in cell shape and the elaboration of filopodial extensions.
These results provide the first direct demonstration that
the S518D merlin mutation, which mimics merlin
phosphorylation, impairs not only merlin growth and
motility suppression but also leads to an acquisition of a
novel phenotype previously ascribed to ERM proteins.NF2) tumor suppressor gene
product, merlin, belongs to the ezrinradixinmoesin
(ERM) subgroup of the Protein 4.1 family, which links
cell surface glycoproteins to the actin cytoskeleton.
Previous studies have suggested that phosphorylation of
merlin, similar to other ERM proteins, may regulate its
function. To determine whether merlin phosphorylation
has functional consequences for merlin suppression of cell
growth and motility, we generated doxycycline-regulatable
RT4 schwannoma cell lines that inducibly express
full-length merlin with mutations at two potential
phosphorylation sites (amino-acid residues S518 and
T576). Whereas a mutation at S518 that mimics
constitutive phosphorylation (S518D) abrogates the ability
of merlin to suppress cell growth and motility, the
S518A merlin mutant, which mimics nonphosphorylated
merlin, functions equivalently to wild-type merlin. Similar
mutations involving T576, the analogous phosphorylation
site in ERM proteins important for regulating their
function, had no effect. In contrast to other functionally
inactive missense merlin mutants, the regulated overexpression
of S518D merlin resulted in dramatic changes
in cell shape and the elaboration of filopodial extensions.
These results provide the first direct demonstration that
the S518D merlin mutation, which mimics merlin
phosphorylation, impairs not only merlin growth and
motility suppression but also leads to an acquisition of a
novel phenotype previously ascribed to ERM proteins.