Abstract:
:The protein kinase B-RAF is mutated in approximately 7% of human cancers. Most mutations are activating, but, surprisingly, a small number have reduced kinase activity. However, the latter can still stimulate cellular signaling through the MEK-ERK pathway because they activate the related family member C-RAF. We examine the mechanism underlying C-RAF activation by B-RAF. We show that C-RAF is activated in the cytosol in a RAS-independent manner that requires activation segment phosphorylation and binding of 14-3-3 to C-RAF. We show that wild-type B-RAF forms a complex with C-RAF in a RAS-dependent manner, whereas the mutants bind independently of RAS. Importantly, we show that wild-type B-RAF can also activate C-RAF. Our data suggest that B-RAF activates C-RAF through a mechanism involving 14-3-3 mediated heterooligomerization and C-RAF transphosphorylation. Thus, we have identified a B-RAF-C-RAF-MEK-ERK cascade that signals not only in cancer but also in normal cells.
journal_name
Mol Celljournal_title
Molecular cellauthors
Garnett MJ,Rana S,Paterson H,Barford D,Marais Rdoi
10.1016/j.molcel.2005.10.022subject
Has Abstractpub_date
2005-12-22 00:00:00pages
963-9issue
6eissn
1097-2765issn
1097-4164pii
S1097-2765(05)01717-Xjournal_volume
20pub_type
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