CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation.
Mol Cell
; 31(6): 862-72, 2008 Sep 26.
Article
in En
| MEDLINE
| ID: mdl-18922468
ABSTRACT
The CRAF protein kinase regulates proliferative, differentiation, and survival signals from activated RAS proteins to downstream effectors, most often by inducing MEK/ERK activation. A well-established model of CRAF regulation involves RAS-mediated translocation of CRAF to the plasma membrane, where it is activated by a series of events including phosphorylation. Here we have discovered a new mode of regulation that occurs prior to this step. By creating a kinase-defective version of CRAF in mice or by use of the RAF inhibitor sorafenib, we show that CRAF must first undergo autophosphorylation of serine 621 (S621). Autophosphorylation occurs in cis, does not involve MEK/ERK activation, and is essential to ensure the correct folding and stability of the protein. In the absence of S621 phosphorylation, CRAF is degraded by the proteasome by mechanisms that do not uniquely rely on the E3 ubiquitin ligase CHIP.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphoserine
/
Protein Processing, Post-Translational
/
Proto-Oncogene Proteins c-raf
/
Proteasome Endopeptidase Complex
Limits:
Animals
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2008
Type:
Article
Affiliation country:
United kingdom