In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2346-2346
Abstract:
The Ras/RAF/MEK/ERK signaling pathway (MAPK pathway) plays a major role in growth factor-mediated cell proliferation and is frequently activated by mutation in human cancers. The precise mechanism of pathway activation is dependent on the underlying mutation. Thus, the recurrent B-RAFV600E mutation, which is found in more than 60% of melanomas, promotes MAPK pathway signaling independent of RAS activation whereas activating K-RAS mutations drive MAPK signaling through C-RAF activation. The hallmarks of C-RAF activation include B and C-RAF heterodimerization, membrane localization and C-RAF phosphorylation. In this work, we have discovered that in addition to its ability to activate the pathway through B-RAF/C-RAF dimerization, B-RAF suppresses the MAPK pathway through formation of a stable B-RAF/MEK complex in the cytoplasm of B-RAFWT and K-RAS mutant (K-RASMT) tumor lines. To understand the molecular mechanism of the B-RAF/MEK interaction, we have determined the crystal structure of a heterotetrameric B-RAF:MEK1 complex in which B-RAF and MEK1 form a face-to-face dimer with B-RAF side-to-side dimers at the heart of the complex. Structural and biochemical evidence illustrate that the molecular determinants for B-RAF enzymatic activity is distinct from those required for interaction with MEK. Our work also reveals the molecular basis for the paradoxical ability of both BRAF-activating and -inactivating oncogenic mutations to stimulate the MAPK pathway. Taken together, these findings reveal a novel regulatory role for B-RAF in the MAPK pathway that is independent of its catalytic activity but dependent on the conformation of the B-RAF kinase domain. Citation Format: Malek Shiva, Jacob R. Haling, Jawahar Sudhamsu, Tony Morales, Ariana Peck, Ivana Yen, Barbara Brandhuber, Sarah Hymowitz. A B-RAF-MEK complex reveals a kinase-independent role for BRAF in MAPK pathway suppression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2346. doi:10.1158/1538-7445.AM2013-2346
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-2346
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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