Merlin suppresses the SRE-dependent transcription by inhibiting the activation of Ras-ERK pathway.
The neurofibromatosis type 2 (NF2) gene encodes an intracellular membrane-associated protein called merlin or schwannomin, which is known to be a tumor suppressor. Numerous studies have suggested that merlin is involved in the regulation of cell growth and proliferation. Previously, merlin/schwannomin was reported to block Ras-induced cell proliferation and anchorage-independent cell growth. Also, the N-terminus of merlin was found to suppress cell proliferation, although it appears to be less effective than full-length merlin. However, the inhibitory mechanism of merlin is unknown. In this report, merlin is shown to be effective at suppressing serum/Ras-induced and Elk-mediated SRE dependent transactivation, and serum-induced ERK phosphorylation in NIH3T3 cells. In addition, merlin inhibited serum-induced Elk phosphorylation, a downstream effector of ERKs. Also, the N-terminal deficient merlin mutant could not block serum-induced and Elk-mediated SRE dependent transactivation, although the C-terminal deficient merlin mutant could. These results suggest that merlin inhibits SRE dependent transactivation by repressing serum-induced ERK phosphorylation and its downstream effector, Elk phosphorylation. Also, the N-terminus of merlin may be important for its inhibitory effect. Our results show that merlin acts as a negative regulator of the SRE signaling pathway via the Ras-ERKs pathway.
Lim
Jung Yeon
JY
Neuroscience Genome Research Center, The Catholic University of Korea, Seoul, Republic of Korea.
Kim
Hongtae
H
Kim
Young Hoon
YH
Kim
Sae Woong
SW
Huh
Pil-Woo
PW
Lee
Kweon-Haeng
KH
Jeun
Sin-Soo
SS
Rha
Hyoung Kyun
HK
Kang
Joon-ki
JK
D016475:3T3 Cells; D000818:Animals; D004789:Enzyme Activation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025581:Neurofibromin 2 / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D036225:Receptor, EphB1 / Q000378:metabolism / Q000502:physiology; D027602:Serum Response Element / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D025581:Neurofibromin 2; D036225:Receptor, EphB1; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins