The Phosphorylation status of merlin is important for regulating the Ras-ERK pathway.
The neurofibromatosis type2 (NF2) tumor suppressor gene product, merlin, is structurally related to the ezrin-radixin-moesin (ERM) family of proteins that anchor the actin cytoskeleton to specific membrane proteins and participate in cell signaling. However, the basis of the tumor suppressing activity of merlin is not well understood. Previously, we identified a role of merlin as an inhibitor of the Ras-ERK signaling pathway. Recent studies have suggested that phosphorylation of merlin, as of other ERM proteins, may regulate its function. To determine whether phosphorylation of merlin affects its suppression of Ras-ERK signaling, we generated plasmids expressing full-length merlin with substitutions of serine 518, a potential phosphorylation site. A substitution that mimics constitutive phosphorylation (S518D) abrogated the ability of merlin to suppress effects of the Ras-ERK signaling pathway such as Ras-induced SRE transactivation, Elk-mediated SRE transactivation, Ras-induced ERK phosphorylation and Ras-induced focus formation. On the other hand, an S518A mutant, which mimics nonphosphorylated merlin, acted like wild type merlin. These observations show that mimicking merlin phosphorylation impairs not only growth suppression by merlin but also its inhibitory action on the Ras-ERK signaling pathway.
Jung
Ju Ri
JR
Department of Neurosurgery, The Catholic University of Korea, Seoul 137-701, Korea.
Kim
Hongtae
H
Jeun
Sin-Soo
SS
Lee
Joo Yong
JY
Koh
Eun-Jeoung
EJ
Ji
Cheol
C
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D027602:Serum Response Element / Q000235:genetics; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000235:genetics; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D025581:Neurofibromin 2; D050807:ets-Domain Protein Elk-1; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins