Merlin cooperates with neurofibromin and Spred1 to suppress the Ras-Erk pathway.
Hum Mol Genet
; 29(23): 3793-3806, 2021 02 04.
Article
em En
| MEDLINE
| ID: mdl-33331896
ABSTRACT
The Ras-Erk pathway is frequently overactivated in human tumors. Neurofibromatosis types 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain (RBD) and the kinase domain (KiD) of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a 'selective Ras barrier'. Merlin-deficient Schwann cells require the Ras-Erk pathway activity for proliferation. Accordingly, suppression of the Ras-Erk pathway likely contributes to merlin's tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Células de Schwann
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Proteínas ras
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Neurofibromina 1
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Neurofibromina 2
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MAP Quinases Reguladas por Sinal Extracelular
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article