Merlin inhibits growth hormone-regulated Raf-ERKs pathways by binding to Grb2 protein.
Numerous studies have suggested that the NF2 protein merlin is involved in the regulation of abnormal cell growth and proliferation. In this study, to better understand the merlin's mechanisms that contribute to the inhibition of tumorigenesis, we examined the potential action of merlin on the cell proliferative signaling pathways in response to growth hormone (GH). Merlin effectively attenuated the GH-induced serum response element (SRE) and Elk-1-mediated transcriptional activation, as well as the endogenous SRE-regulated gene c-fos expression in NIH3T3 cells. In addition, merlin prevented the Raf-1 complex activation process, which resulted in the suppression of MAP kinase/ERK, extracellular signal-regulated kinase (ERKs), and Elk-1 phosphorylation, which are the downstream signals of Raf-1. Moreover, it was shown that merlin interacted with endogenous growth factor receptor bound 2 (Grb2) protein and inhibited its expression. These results suggest that merlin contributes, via its protein-to-protein interaction with Grb2 and consequent inhibition of the MAPK pathways, to the regulation of the abnormal cell proliferation, and this provides a further mechanism underlying the tumor suppressor function of merlin.
Lim
Jung Yeon
JY
Department of Neurosurgery, The Catholic University of Korea, Seoul 137-701, Republic of Korea, and Department of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Kim
Hongtae
H
Jeun
Sin-Soo
SS
Kang
Seok-Gu
SG
Lee
Kyung-Jin
KJ
D000818:Animals; D004305:Dose-Response Relationship, Drug; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D013006:Growth Hormone / Q000008:administration & dosage* / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D025581:Neurofibromin 2 / Q000378:metabolism*; D011485:Protein Binding; D048490:raf Kinases / Q000378:metabolism*
D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D025581:Neurofibromin 2; D013006:Growth Hormone; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases