INVESTIGADORES
SURACE Ezequiel Ignacio
artículos
Título:
Serine 518 phosphorylation modulates merlin intramolecular association
Autor/es:
RONG RONG, EZEQUIEL I SURACE, CARRIE A HAIPEK, DAVID H GUTMANN AND KEQIANG YE
Revista:
ONCOGENE
Editorial:
Nature Publishing Group
Referencias:
Año: 2004 p. 8447 - 8454
ISSN:
0950-9232
Resumen:
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-aminoterminal
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.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-aminoterminal
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.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.