| First Author | Cui Y | Year | 2021 |
| Journal | Hum Mol Genet | Volume | 29 |
| Issue | 23 | Pages | 3793-3806 |
| PubMed ID | 33331896 | Mgi Jnum | J:338790 |
| Mgi Id | MGI:7514717 | Doi | 10.1093/hmg/ddaa263 |
| Citation | Cui Y, et al. (2021) Merlin cooperates with neurofibromin and Spred1 to suppress the Ras-Erk pathway. Hum Mol Genet 29(23):3793-3806 |
| abstractText | 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. |
