التفاصيل البيبلوغرافية
| العنوان: |
Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation |
| المؤلفون: |
Pan-Yu Chen, Benjamin J. Huang, Max Harris, Christopher Boone, Weijie Wang, Heidi Carias, Brian Mesiona, Daniela Mavrici, Amanda C. Kohler, Gideon Bollag, Chao Zhang, Ying Zhang, Kevin Shannon |
| المصدر: |
JCI Insight, Vol 8, Iss 17 (2023) |
| بيانات النشر: |
American Society for Clinical investigation, 2023. |
| سنة النشر: |
2023 |
| المجموعة: |
LCC:Medicine |
| مصطلحات موضوعية: |
Oncology, Medicine |
| الوصف: |
A T50I substitution in the K-Ras interswitch domain causes Noonan syndrome and emerged as a third-site mutation that restored the in vivo transforming activity and constitutive MAPK pathway activation by an attenuated KrasG12D,E37G oncogene in a mouse leukemia model. Biochemical and crystallographic data suggested that K-RasT50I increases MAPK signal output through a non-GTPase mechanism, potentially by promoting asymmetric Ras:Ras interactions between T50 and E162. We generated a “switchable” system in which K-Ras mutant proteins expressed at physiologic levels supplant the fms like tyrosine kinase 3 (FLT3) dependency of MOLM-13 leukemia cells lacking endogenous KRAS and used this system to interrogate single or compound G12D, T50I, D154Q, and E162L mutations. These studies support a key role for the asymmetric lateral assembly of K-Ras in a plasma membrane–distal orientation that promotes the formation of active Ras:Raf complexes in a membrane-proximal conformation. Disease-causing mutations such as T50I are a valuable starting point for illuminating normal Ras function, elucidating mechanisms of disease, and identifying potential therapeutic opportunities for Rasopathy disorders and cancer. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2379-3708 |
| Relation: |
https://doaj.org/toc/2379-3708 |
| DOI: |
10.1172/jci.insight.168445 |
| URL الوصول: |
https://doaj.org/article/4f2c72c0deff4793984c39f4fb3606d1 |
| رقم الانضمام: |
edsdoj.4f2c72c0deff4793984c39f4fb3606d1 |
| قاعدة البيانات: |
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