Click here to close Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly. We suggest using a current version of Chrome, FireFox, or Safari.
XB-ART-2433
Mol Cell. January 21, 2005; 17 (2): 215-24.

Regulation of Raf-1 by direct feedback phosphorylation.

Dougherty MK , Müller J , Ritt DA , Zhou M , Zhou XZ , Copeland TD , Conrads TP , Veenstra TD , Lu KP , Morrison DK .


Abstract
The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Because of its integral role in cell signaling, Raf-1 activity must be precisely controlled. Previous studies have shown that phosphorylation is required for Raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of Raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli. The hyperphosphorylated/desensitized Raf-1 is subsequently dephosphorylated and returned to a signaling-competent state through interactions with the protein phosphatase PP2A and the prolyl isomerase Pin1. These findings elucidate a critical Raf-1 regulatory mechanism that contributes to the sensitive, temporal modulation of Ras signaling.

PubMed ID: 15664191
Article link: Mol Cell.
Grant support: R01GM58556 NIGMS NIH HHS

Genes referenced: mapk1 pin1 ppp2r4 raf1
Antibodies referenced:

My Xenbase: [ Log-in / Register ]
version: [3.2.1]


Major funding for Xenbase is provided by the National Institute of Child Health and Human Development, grant P41 HD064556